A case of Kaposi sarcoma with immune reconstitution inflammatory syndrome.
HISTORY OF PRESENT ILLNESS
The patient is a 28-year-old man with a history of newly diagnosed HIV/AIDS, complaining of a new rash on his abdomen and right arm. Initially, he presented to the emergency depart- ment with fever, weakness, and diarrhea and was admitted with sepsis. Upon admission, his serum creatinine level was 4.49 mg/dL and his serum sodium level was 117 mEq/L. A computed tomography scan of the abdomen and pelvis showed evidence of pancolitis. The patient was started on intravenous fluid and antibiotics. Although he was improving clinically, he left against medical advice, 1 day after admis- sion. At that time, he was provided with prescriptions for levofloxacin and metronidazole, both of which he reported taking as directed.
Shortly after the patient left the hospital, he was contacted regarding a positive HIV screening test result. The following day, he presented to the Partnership Comprehensive Care Practice for a new patient visit. During that visit, he reported his diarrhea had improved, but he continued to complain of fever, weakness, nausea, coughing, wheezing, and dyspnea. On physical examination, and his temperature was 99.9 degrees F. His blood pressure was 88/59 mm Hg, his heart rate was 153 bpm, with normal respiratory rate and oxygen saturation. Given his hemodynamic instability, he was returned to the hospital via emergency medical services.
During the patient’s second hospital stay, he was started on broad-spectrum antibiotics. The result of his chest x-ray was negative. Blood and urine cultures were negative. CD4 count was 3 cells/μL. The patient underwent a lumbar puncture, and the cerebrospinal fluid was remarkable for a positive Venereal Disease Research Lab test result. His antibiotics were narrowed to intravenous penicillin for neurosyphilis, and he received the full 14-day course as an inpatient. He defervesced and became hemodynamically stable. In the hospital, the patient was started on emtricitabine, tenofovir disoproxil fumarate, and dolutegravir as well as trimethoprim/sulfamethoxazole for prophy- laxis. He was also started on gabapentin for lower extremity paresthesias and was discharged with these medications.
One day after discharge, the patient returned to the clinic for a hospital follow-up. He reported 100% adherence to all medications since discharge. He reported control of his lower extremity symptoms with gabapentin. His gastrointestinal (GI) symptoms and cough had resolved. However, he now complained of a new skin rash on the left side of his chest, left shin, and right forearm that developed during the course of his hospitalization. He did not know exactly when the lesions had appeared, but to his knowledge, they had not changed in size since he first noticed them. He did not complain of pain, itching, tenderness to touch, swelling, or redness and denied skin lesions anywhere else on his body. The patient denied fever, chills, night sweats, shortness of breath, difficulty breathing, nausea, vomiting, abdominal pain, diarrhea, or constipation.
The patient was afebrile and hemodynamically stable with a normal respiratory rate and normal oxygen saturation. Body mass index was 19.8. His skin exam was significant for red-purple nodules on the left side of his torso, right forearm, and left shin (Figure 1 a-c). In general, the patient was in no acute distress. His eyes were anicteric with normal conjunctivas. Pupils were equal, round, and reactive to light. He was awake, alert, and oriented with a normal mood and affect. His oropharynx was without erythema, exudates, or patches. His neck was supple and symmetric, with no palpable thyroid abnormality or cervical lymphadenopathy. Lungs were clear to auscultation with normal respiratory effort. His heart sounds were regular in rate and rhythm without murmurs, rubs, or gallops. He had no peripheral edema and his abdomen was soft, nontender, and nondis- tended, with normal bowel sounds. He had full range of motion in all extremities, with diminished strength in his bilateral lower extremities and ataxia.
The patient’s laboratory studies, collected during the initial outpatient visit were significant for HIV genotype without resistance, a viral load of 899,000 copies/mL, and a CD4 count of 4 cells/μL. Hepatitis C and hepatitis A antibody test results were negative. The hepatitis B surface antigen was negative and the hepatitis B surface antibody was positive. The patient had a negative toxoplasmosis immunoglobulin test result. His rapid plasma reagin test result was positive with a 1:128 titer and the fluorescent treponemal antibody test result was positive. His white blood cell count was 8.5 x 103 cells/ μL; hemoglobin, 10.2 g/dL; hematocrit, 32.7%; and platelets, 183 x 103 cells/μL. His alkaline phosphatase level was 51 U/L; aspartate transaminase, 82 IU/L; and alanine transaminase, 33 IU/L. The patient had elevated triglycerides and low high-density lipoprotein cholesterol.
DIAGNOSTIC PROCEDURES AND RESULTS
The patient’s inpatient HIV regimen was discontinued, and he was started on bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy). All other medications were continued. The patient was referred to a dermatologist for suspicion of Kaposi sarcoma (KS). Based on the lesions’ appearance, the dermatologist believed that the patient’s lesions were cuta- neous KS, likely worsened in the setting of immune recon- stitution inflammatory syndrome (IRIS), and a biopsy was ordered. The biopsy confirmed the diagnosis of KS.
TREATMENT AND FOLLOW-UP
The patient was referred to an oncologist, who recommended management of the KS with antiretroviral therapy (ART) alone. One month after discharge, the lesions had decreased in size significantly and the patient’s CD4 count had recovered to 128 cells/μL. An outpatient colonoscopy is being arranged, given his initial symptoms.
KS is a low-grade vascular tumor associated with infection with human herpesvirus 8. It is the most common type of tumor in individuals infected with HIV, is considered an AIDS-defining illness, and is a significant cause of morbidity and mortality.1 Among patients with HIV who were infected with both HIV and human herpesvirus 8 at baseline, the 10-year probability of developing KS was approximately 50%.2 Since the introduction of ART for patients with HIV infection, the incidence of all opportunistic infections including KS has significantly declined along with overall mortality.1,3 However, initiation of ART has also been demonstrated to be associated with reactivation of indolent infections, including KS, in a process known as IRIS. IRIS is thought to be the direct result of a partially restored immune system recognizing pathogens or antigens that were previously present, but clinically asymptomatic.1 Here, we report a case of KS presenting in a patient upon ART initiation.
Cutaneous disease is the most common form of KS.4 The lesions most often appear on the lower extremities, face, oral mucosa, and genitalia. Lesions are not painful or pruritic, may be pink, red, purple, or brown due to their vascularity, are most often papular, and range from several millimeters to centimeters in diameter. Visceral disease most frequently presents in the GI and respiratory systems and can occur even without cutaneous disease.5 GI lesions may be asymptomatic or cause weight loss, abdom- inal pain, nausea, vomiting, upper or lower GI bleeding, malabsorption, intestinal obstruction, and/or diarrhea.5 Screening for GI involvement involves testing for stool occult blood, whereas endoscopy is reserved for patients who test positive for occult blood or have GI symptoms.5 Pulmonary KS lesions can cause shortness of breath, cough, fever, hemoptysis, or chest pain and are screened via chest x-ray. Bronchoscopy is reserved for those with abnormal imaging test results and persistent respiratory symptoms with no other cause.5 Diagnosis of cutaneous and visceral disease should be confirmed by biopsy.5
Combination ART is recommended for treatment of all patients with AIDS-related KS, and since its introduction, the incidence of KS in patients who are HIV positive has significantly declined.4 However, initiating HIV treatment has also been shown to be associated with progression of KS in the setting of presumed IRIS.3 IRIS is described as an intense inflammatory reaction to foreign antigens caused by the rapid recovery of the immune system upon ART initiation in patients with very advanced HIV, who often have presented late for care and may have AIDS- defining opportunistic infections.6 Patients with IRIS present with an “unmasking” flare-up of an underlying previously undiagnosed opportunistic infection or a “paradoxical” worsening of a previously treated opportunistic infection that causes progressive clinical deterioration.6 This flare-up occurs despite markers of clinical improvement in HIV infection such as decreased viral load and increased CD4 count. IRIS is usually self-limiting but can cause significant morbidity and even mortality if not promptly recognized and treated.6
Significant proportions (7%-30%) of patients with KS have been shown to develop IRIS, presenting with increased KS inflammation and/ or edema in the initial weeks after ART initiation or change in ART regimen following treatment failure.7 In a study by Bower et al,2 of 150 therapy-naïve patients who presented with KS, 10 (6.6%) developed progression of KS within 3 to 6 weeks of starting ART. In a study by Yanik et al,8 the incidence of KS was highest during the first 6 months after ART initiation and was asso- ciated with a lower CD4 count at ART initiation. The same study showed that the incidence of KS dropped significantly with continued treatment, supporting the recommendation that patients should continue ART in the event of developing IRIS-associated KS. One study found that nearly 1out of 3 patients with KS developed IRIS, with a higher incidence in those with visceral compared with cutaneous disease and that visceral IRIS-KS was associated with significant mortality.6 These authors hypothesized that the widely varied rates of IRIS-KS reported among studies may be in part due to the lack of a standardized definition or diagnostic criteria for IRIS. Factors associated with an increased risk of IRIS-associated KS in patients initiating ART for HIV include more extensive KS, a higher HIV viral load, and the use of ART without chemotherapy7 as well as the use of glucocorticoids.9
In addition to ART, treatment can involve local or systemic therapy. Local symptomatic therapy manages existing lesions, but it does not prevent the development of new lesions in untreated areas. This includes intralesional chemotherapy, which induces regression of injected tumors and is preferable for small lesions, as well as radia- tion therapy for treating larger or more numerous lesions.10 Systemic chemotherapy is indicated in the event of extensive cutaneous disease (>25 lesions), symptomatic visceral involvement, cutaneous KS that is unresponsive to local therapy, and patients with progressive disease in the setting of IRIS.10 Several small random- ized trials have investigated the treatment of KS with chemotherapy plus ART versus ART alone. For example, chemotherapy plus ART has been shown to increase rates of disease regression and reduce rates of disease progression, especially in the treatment of severe or progressive disease. However, to date, no increase in survival or overall morbidity has been demonstrated.11,12
In conclusion, this case report represents an additional example of the well-described phenomenon of progressive KS in the setting of IRIS upon ART initiation in a patient with AIDS. In resource-rich settings, further research is needed to diagnose such patients earlier, before the development of KS.
DiCenzo is a fourth-year medical student at Drexel University College of Medicine. She plans to pursue a residency in obstetrics and gynecology and is interested in family planning, HIV, harm reduction, and trauma-informed care.Forrestel is an assistant professor of clinical dermatology at the University of Pennsylvania in Philadelphia, Pennsylvania.Coppock is an assistant professor of medicine at Drexel University College of Medicine. He provides primary care at the Partnership Comprehensive Care Practice.
1. Bower M, Nelson M, Young AM, et al. Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma. J Clin Oncol. 2005;23(22):5224-5228. doi: 10.1200/JCO.2005.14.597.
2. Martin JN, Ganem DE, Osmond DH, et al. Sexual transmission and the natural history of human herpesvirus 8 infection. N Engl J Med. 1998;338(14):948-954. doi: 10.1056/NEJM199804023381403.
3. Engels EA, Pfeiffer RM, Goedert JJ, et al. Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS. 2006;20(12):1645. doi: 10.1097/01.aids.0000238411.75324.59.
4. World Health Organization. Guidelines on the treatment of skin and oral HIV-associated conditions in children and adults. Chapter 4. Evidence and recommendations on Kaposi sarcoma (KS). Geneva: World Health Organization; 2014.
5. Etemad BS, Dewan AK. Kaposi sarcoma updates. Dermatol Clin. 2019;37(4):505-517. doi:10.1016/j.det.2019.05.008.
6. Achenbach CJ, Harrington RD, Dhanireddy S, Crane HM, Casper C, Kitahata MM. Paradoxical immune reconstitution inflammatory syndrome in HIV-infected patients treated with combination antiretroviral therapy after AIDS-defining opportunistic infection. Clin Infect Dis. 2012;54(3):424-433. doi: 10.1093/cid/cir802.
7. Letang E, Lewis JJ, Bower M, et al. Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK. AIDS. 2013;27(10):1603-1013. doi: 10.1097/QAD.0b013e328360a5a1.
8. Yaniek EL, Napravnik S, Cole S, et al. Incidence and timing of cancer in HIV-infected individuals following initiation of combination antiretroviral therapy. Clin Infect Dis. 2013;57(5):756-764.
9. Fernandez-Sanchez M, Iglesias MC, Ablanedo-Terrarazas Y, et al. Steroids are a risk factor for Kaposi's sarcoma-immune reconstitution inflammatory syndrome and mortality in HIV infection. AIDS. 2016;30(6):909-914. doi: 10.1097/QAD.0000000000000993.
10. Goncalves PH, Uldrick TS, Yarchoan R. HIV-associated Kaposi sarcoma and related diseases. AIDS. 2017;31(14):1903-1916. doi: 10.1097/QAD.0000000000001567.
11. Gbabe OF, Okwundu CI, Dedicoat M, et al. 2014.Treatment of severe or progressive Kaposi's sarcoma in HIV-infected adults. Cochrane Database Syst Rev. 2014;(9):CD003256.
12. Mosam A, Shaik F, Uldrick TS. 2012. A randomized controlled trial of highly active antiretroviral therapy versus highly active antiretroviral therapy and chemotherapy in therapy-naive patients with HIV-associated Kaposi sarcoma in South Africa. J Acquir Immune Defic Syndr. 2012;60(2):150-157. doi: 10.1097/QAI.0b013e318251aedd.
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