Paradoxical immune reconstitution inflammatory syndrome (IRIS) of Kaposi sarcoma in an HIV-infected African man

Elisa Rae L. Coo, MDa; Maricarr Pamela M. Lacuesta-Gutierrez, MD, FPDSb

Introduction: The immune reconstitution inflammatory syndrome (IRIS) is a reaction that occurs against persistent infectious or non-infectious antigens upon initiation of highly active antiretroviral therapy (HAART).

Case Summary: We report a case of an African male with Kaposi Sarcoma (KS) localized on his right leg as an initial presentation of HIV infection. One month after starting HAART, there was increase in leg edema and rapid worsening of his leg lesions which was consistent with KS-associated IRIS. After assessment for dissemination, the patient continued treatment with HAART without chemotherapy.

Conclusion: KS-associated IRIS should not be mistaken as failure of treatment with HAART. Continuing therapy with HAART alone together with careful monitoring in a patient classified as good risk may be a beneficial option in resource limited situations.

Keywords: Kaposi Sarcoma, KS, Immune reconstitution inflammatory syndrome, IRIS

INTRODUCTION

Immune reconstitution inflammatory syndrome (IRIS) is worsening of the clinical status of an HIV patient upon recovery of the immune system leading to reactivation

of clinical manifestations associated with infectious or noninfectious agents.1 Kaposi sarcoma (KS) has been estimated to lead to IRIS in 6.4-31% of cases after initiation of highly active antiretroviral therapy (HAART).1-3 Based on the Philippine Dermatological Society Health Information System for 2011-2016, there have been 40 recorded cases of Kaposi Sarcoma with a male to female ratio of 19:1.4

CASE REPORTS

A 46-year-old African male presented with a six-month history of pitting edema on the right lower extremity accompanied by firm purplish-brown papules and nodules. Some of the lesions progressed to become tender pinkish red fungating masses coalescing to plaques with sero-purulent foul smelling discharge (Fig. 1). He sought consult with a primary physician who prescribed several courses of antibiotics but did not improve his condition. He was subsequently referred to our institution for management. Aside from the lesions and edema on the right lower extremity, the rest of the physical examination was unremarkable. The patient was otherwise in apparent good health with no history of fever, cough, involuntary weight loss and previous hospitalizations. He denied illicit drug use and but admitted having multiple sexual partners, all of whom were of the opposite sex.

Dermoscopic examination of the papules and nodules showed the characteristic rainbow pattern under polarizing light (Fig. 2). Hematoxylin and eosin stained slides revealed a dermal nodule with spindle cell proliferation of endothelial cells forming slit-like and jagged vascular spaces with extravasation of red blood cells (Fig. 3a-b). Immunohistochemical stains with CD34 and CD31 yielded positive staining of the spindle cells (Fig. 3c-d). The clinical, dermoscopic and histopathologic findings were consistent with a diagnosis of Kaposi sarcoma.

Screening test for human immunodeficiency virus (HIV) was reactive and was confirmed by Western Blot analysis. CD4 count was 220cells/µL. Chest radiography was unremarkable and radiographic exam of the right leg did not show bone involvement. Tests for other infections, including tuberculosis polymerase chain reaction, fungal cultures, Hepatitis B virus, Hepatitis C virus and VDRL were negative.

After unremarkable baseline laboratory workup, the patient was started on efavirenz based anti-retroviral therapy and prophylactic isoniazid therapy. One month later, there was a rapid increase in the number and size of the lesions which was consistent with paradoxical KS-associated immune reconstitution inflammatory syndrome. Repeat chest radiologic exams were negative for metastasis. The patient is currently being managed with HAART alone and monitored for signs of dissemination.

DISCUSSION

KS is an angioproliferative disorder of endothelial cells caused by the human herpesvirus-8(HHV-8).5 KS appears as bluish-red macules, firm plaques or nodules, and may also appear as bullae or fungating forms. It has four subtypes: (1) classic, (2) African endemic, (3) iatrogenic or associated with immunosuppressive therapy, and (4) epidemic or AIDS KS.6,7 Our patient was born and raised in Central Africa. He has been staying in the Philippines for the last ten years with a history

Department of Dermatology, Southern Philippines Medical CenteraResident physician b Consultant

Source of funding: noneConflict of interest: none Corresponding author: Elisa Rae L. Coo, MDEmail: elisaraecoo@yahoo.com

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Figure 3. Hematoxyl in and eosin stain of biopsy specimen taken from a purplish brown nodule s h o w i n g s p i n d l e c e l l proliferation of endothelial cells forming slit-like and jagged vascular spaces with extravasation of red blood cells. (a) 100x magnification (b) 400x magnification. Immunohistochemistry showing strongly positive C D 3 4 ( c ) a n d w e a k l y positive CD31 (d) (400x magnification).

Figure 2. Dermoscopic exam of a nodule on the sole of the right foot (a) and nodule on the right leg (b) showing multicolored areas corresponding to the rainbow pattern in polarized light.

Figure 1. Right lower extremity edema (a) with multiple firm purplis- brown nodules (b) and multiple pinkish red nodules some coalescing to plaques with purulent discharge (c).

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of travel to several European and Asian countries. Initially, our patient correlates clinically with the African subtype but subsequent HIV screening was positive, hence the diagnosis of AIDS KS.

Nodular lesions of KS appear as monomorphic spindle cell proliferations of endothelial cells arranged in bundles and interlacing fascicles with irregular slit-like spaces containing red blood cells.8 Immunohistochemical stains for KS include CD34, CD41, D2-40 (podoplanin) and test for HHV-8.

Dermoscopic examination of papules and nodules under polarized light exhibit the characteristic rainbow pattern which were also seen in our patient. This multicolored pattern with varying dimensions and intensity has been attributed to the presence of abundant hyaline globules in the nodular stage of KS.9

While there is currently no officially accepted staging criteria for Kaposi Sarcoma, a commonly used system is the AIDS Clinical Trials Group (ACTG) criteria.10 The ACTG system includes three variables: tumor extent (T), immune status (I), and systemic symptoms (S). Each variable is then classified as either poor (1) or good (0) risk. Based on the criteria, our patient had an overall good risk since the KS lesions were confined to the skin, CD4 count was above ≥200/µL and no systemic illnesses were identified. For KS patients with HIV, especially those classified as good risk, HAART is considered as first line therapy.6 No clinical trials have been done to assess the efficacy of different HAART regimens for the treatment of Kaposi sarcoma patients with HIV.6 Protease inhibitor (PI) containing regimens have been considered by some authors as the ideal HAART regimen stating that it can diminish HIV transactivating protein Tat

and has some direct antiangiogenic properties. Several non-randomized clinical studies, however, have shown that non-nucleoside reverse-transcriptase inhibitor (NNRTI-) and PI-based regimens were not significantly different in preventing or treating KS in HIV patients.11 In our case, the patient was initiated on NNRTI based 3-in-1 therapy (efavirenz, lamivudine, and tenofovir).

One month after treatment, our patient presented with increased lymphedema and rapid worsening in the number and size of his skin lesions (Figure 4).

IRIS is the worsening of a patient’s clinical status as a result of the immune system regaining its ability to recognize and mount an immune response against infectious and non-infectious agents.12 IRIS may lead to worsening of an existing condition (paradoxical IRIS) or may lead to new onset signs and symptoms from a previously subclinical infection or tumor (unmasking IRIS).13 KS-associated IRIS has been noted to occur in 7-31% of KS cases.3 KS-associated IRIS cases have been diagnosed using varying criteria and attempts to standardize the definition have been made. The standardized KS-associated IRIS criteria by Letang et al consists of: 1. Abrupt KS worsening after ART; 2. Occurrence of worsening within 3 months of ART; 3. Reduction in human immunodeficiency virus load of >1 log10 from pre-ART levels; 4. Agreement of two primary clinicians; and 5. Exclusion of other causes of worsening. In our case, there was abrupt worsening of the patient’s lesions within one month of therapy and follow up assessment along with laboratory and radiologic workup excluded other possible causes of worsening. Viral load testing is not readily available in our area but the authors along with the oncology and infectious disease service physicians

Figure 4. Increase in right lower leg edema, number and size of lesions were noted one month after initiation of antiretroviral therapy.

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REFERENCES

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2. Müller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010; 10(4):251-61.

3. Letang E, Naniche D, Bower M, Miro JM. Kaposi sarcoma-associated immune reconstitution inflammatory syndrome: in need of a specific case definition. Clin Infect Dis. 2012; 55:157-158.

4. Philippine Dermatological Society Health Information System. Philippine Dermatological Society. C2011 [updated August 6, 2017; cited August 10, 2017]. Available by request from pdshis@outlook.com

5. Du M, Bacon CM, Isaacson PG. Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 and lymphoproliferative disorders. J Clin Pathol. 2007; 60(12):1350-1357. doi:10.1136/jcp.2007.047969.

6. La Ferla L, Pinzone MR, Nunnari G, Martellotta F, Lleshi A, Tirelli U, et al. Kaposi’ s sarcoma in HIV-positive patients: the state of art in the HAART-era. Eur Rev Med Pharmacol Sci. 2013; 17(7):2354-2365.

7. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw-Hill; 2012.

8. Grayson W, Pantanowitz L. Histological variants of cutaneous Kaposi sarcoma. Diagn Pathol. 2008; 3:31. doi:10.1186/1746-1596-3-31.

9. Satta R, Fresi L, Cottoni F. Dermoscopic rainbow pattern in Kaposi’s sarcoma lesions: our experience. Arch Dermatol. 2012; 148(10):1207-1208. doi:10.1001/archdermatol.2012.2204.

10. Okuku F, Orem J, Kafeero J, Phipps W, Kamya MR, Casper C. Evaluation of the AIDS clinical trials group staging criteria for Kaposi Sarcoma in a resource limited setting. Infect Agent Cancer. 2012; 7(Suppl 1):P8. doi:10.1186/1750-9378-7-S1-P8.

11. Uldrick TS, Whitby D. Update on KSHV-epidemiology, Kaposi sarcoma pathogenesis, and treatment of Kaposi sarcoma. Cancer Lett. 2011; 05:150-162.

12. Murdoch DM, Venter WD, Van Rie A, Feldman C. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Res Ther. 2007; 4:9. doi:10.1186/1742-6405-4-9.

13. Cattelan AM, Mattiolo A, Grassi A, Piano MA, Sasset L, Trevenzoli M, et al. Predictors of immune reconstitution inflammatory syndrome associated with Kaposi’s sarcoma: a case report. Infect Agent Cancer. 2016; 11:5. doi:10.1186/s13027-016-0051-3.

14. Melé-Ninot G, Sola-Ortigosa J, Quintana-Codina M, Iglesias-Sancho M, Delás-Amat J, Salleras-Redonnet M. AIDS-Related Kaposi’s sarcoma and associated immune reconstitution inflammatory syndrome. Clin Microbiol. 2016; 5:236. doi:10.4172/2327-5073.1000236.

15. Mosam A, Shaik F, Uldrick TS, Esterhuizen T, Friedland G, Scadden D, et al. A randomized controlled trial of HAART versus HAART and chemotherapy in therapy-naïve patients with HIV-associated Kaposi sarcoma in South Africa. J Acquir Immune Defic Syndr. 2012; 60(2):150-157. doi:10.1097/QAI.0b013e318251aedd.

16. Volkow P, Cesarman-Maus G, Garciadiego-Fossas P, Rojas-Marin E, Cornejo-Juárez P. Clinical characteristics, predictors of immune reconstitution inflammatory syndrome and long-term prognosis in patients with Kaposi sarcoma. AIDS Res and Ther. 2017; 14:30. doi:10.1186/s12981-017-0156-9.

handling the case agreed that the patient’s manifestations fit the characteristics of KS-associated IRIS.

While some IRIS cases, such as those caused by tuberculosis and cytomegalovirus retinitis, are managed with corticosteroids12, the use of corticosteroids for IRIS in KS in not recommended since it has been shown to promote tumor growth and replication of HHV-8 leading to clinical deterioration.14 For the treatment of KS in HIV patients, HAART combined with chemotherapy versus HAART alone has generally been shown to have similar survival and complete remission outcomes.15,16 Hence, in resource limited areas, therapy with HAART alone accompanied by careful monitoring has important beneficial effects for treating KS-associated IRIS.

The patient is currently being managed with HAART alone and monitored for dissemination.

CONCLUSION

In conclusion, KS-associated IRIS may occur after initiation of HAART. It should not be confused as treatment failure and does not warrant changing or discontinuing the HAART regimen.14 Some studies have shown that HAART in combination with chemotherapy may be a more effective means to treat this condition. However, considering the limited resources available, HAART alone has also shown comparable survival rates and has a beneficial role in treating patients staged as good risk.

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