Concomitant systemic lupus erythematosus and HIV infection

Abstract Rationale: Coexisting systemic lupus erythematosus (SLE) and human immunodeficiency virus (HIV) infection cases are rare worldwide. Great challenges are posed on the diagnosis and treatment of such concurrent cases. Patient concern: We report the case of a 44-year-old Chinese man with edema, hematuria, and fever who presented at West China Hospital, Sichuan University, Chengdu, Sichuan, China, in 2013. Diagnoses: An initial diagnosis of SLE was made from the clinical manifestations and laboratory findings based on the Systemic Lupus International Collaborating Clinics classification criteria. Immunosuppressant therapy relieved him of the edema and hematuria, but he regained the symptoms after a cold. Workup, including electrochemiluminescence immunoassay, western blot, and polymerase chain reaction analysis, revealed that he was concurrently infected with HIV after hospitalization. Interventions: The treatment plan included methylprednisolone and cyclophosphamide, with gastroprotective and hepatoprotective agents, simultaneously aiming to reduce urinary protein. After HIV infection confirmed, cyclophosphamide was stopped. He was referred to the local Centers for Disease Control and Prevention for combination antiretroviral therapy (ART). He was suggested to continue monitoring CD4 T-cell count for an appropriate dose of immunosuppressive drugs. Outcomes: In the last follow-up in May 2017, he had been stable in terms of both SLE and HIV infection. Lessons: The case highlights the presence of concurrent SLE and HIV infection. Laboratory technicians and clinicians should be cautious on diagnosis, especially in eliminating the false-positive results. Attention should be paid to the dose of immunosuppressants and the ART procedure.


Introduction
The coexisting cases of systemic lupus erythematosus (SLE) and human immunodeficiency virus (HIV) infection are rarely reported worldwide; however, studies on such cases may provide insight into the immunopathogenesis of the 2 disease conditions. Moreover, with caution, clinicians should evaluate the safety of SLE therapy based on immunosuppressants in the context of HIV infection. Therefore, interesting diagnostic and therapeutic dilemmas are raised in the case of coexistent SLE and HIV infection. We present a rare concomitant case of SLE and HIV infection, which has never been reported in China. We also provide a literature review and discuss the diagnostic, pathogenetic, and therapeutic implications of the association between these 2 diseases.

Ethics statement
The use of the clinical data in this study has been approved by the Ethical Board of West China Hospital, Sichuan University.
Elecsys HIV Combi assay, a fourth-generation automated electrochemiluminescence immunoassay which is designed for the simultaneous detection of HIV p24 antigen, HIV-1, and HIV-2 antibodies. The analyzer automatically calculates the cutoff values based on the measurement of calibrations and the results are given in the form of a cutoff index (COI). Assay results are presented as ratios of specimen signals to the cutoff value (S/CO). Samples are considered as positive if COI or S/CO ≥1.0, as negative if the COI or S/CO <0.9 and as borderline if COI or S/ CO is between 0.9 and 1.0.

HIV confirmatory tests
The HIV confirmatory tests include western blot HIV blot 2.2 (MP Diagnostics, Singapore) and COBAS AmpliPrep/COBAS TapMan HIV-1 Test (Roche Diagnostics), as is described previously. [2] In China, HIV-1 western blots are usually interpreted following the National Guideline for Detection of HIV/AIDS (2009 edition), which require detection gp41 and gp120/160 (p24 and gp41/gp120/gp160) for positive results. The absence of all bands is a negative result. The result was recorded after reading by 2 different laboratory technologists and according to manufacturer's criteria for interpretation of positive results. Polymerase chain reaction (PCR) (COBAS AmpliPrep/ COBAS TapMan HIV-1 Test, Roche Diagnostics) was used to quantitate HIV RNA levels and was conducted according to manufacturer's instructions. This was found to give a linear response from 48 HIV-1 RNA copies/mL to 10,000,000 HIV-1 RNA copies/mL and a sensitivity of 50 copies/mL across all subtypes ranging from <15 to 46 copies/mL of HIV-1 group M. All

Case report
The patient was a 44-year-old Chinese man. In 2012, he started having headaches and dizziness for over 7 months, facial and edema in both lower limbs for 3 months, and gross hematuria for 1 month. He reported abdominal pain, fever, regurgitation, and belching, with occasional shortness of breath. He visited the local hospital. Complete blood count (CBC) demonstrated a hemoglobin (HGB) level of 64 g/L. Routine urinalysis revealed the following: protein (PRO; 2+), white blood cells (WBCs; 2+, 31/ HP), and red blood cells (RBCs; 3+, 75/HP). His creatine level was 189 mmol/L. Elevated antinuclear antibody (ANA) level (1:320, homogeneous and cytoplasmic), +dsDNA level (1:320), decreased complement component 3 (C3) level (0.366 g/L), and C4 level (0.101 g/L) were confirmed. He was diagnosed as having SLE and SLE lupus nephritis (SLE-LN), and accepted prednisone (60 mg qd) and cyclophosphamide (50 mg bid) treatment in the local hospital. After the inpatient therapy, he was gradually relieved of the edema, headache, dizziness, and abdominal discomfort, but retained bubbling urine. In January 2013, he caught a cold. He regained eyelid and facial edemas after oral intake of penicillin. The edema gradually spread to both lower limbs and the whole body, accompanied by gross hematuria. He was admitted to the Department of Urology, West China Hospital.
A routine pretransfusion test revealed a highly suspected HIVpositive result as HIV electrochemiluminescence immunoassay result was 1,799,000 (cut-off value = 1) cut of index (COI) on January 28, 2013. The CD4 T-cell count was 138 cells/mm 3 , and the CD4 + /CD8 + level was 0.48 (normal, 0.97-2.31). On January 31, 2013, western blot confirmed HIV infection with all bands positive. The HIV viral load (VL) was 491,000 copies/mL. He developed HIV infection with a known SLE history. Considering the low CD4 T-cell count, cyclophosphamide was stopped to reduce the chance of infection.
After the HIV infection was confirmed, cyclophosphamide was stopped. He was discharged and was suggested to transfer to the local Center for Disease Control and Prevention (CDC) for highly active antiretroviral therapy (HAART). The HAART included stavudine (d4T; 40 mg bid), lamivudine (3TC; 150 mg bid), and nevirapine (NVP; 200 mg bid) was initiated immediately. He  [4][5][6][7][8][9] Seven from the pediatric group acquired HIV infection congenitally. One of the children presented initially with manifestations of SLE and then showed signs of congenital HIV infection. [8] Positive lupus serologies, including anti-dsDNA antibodies, were found in these cases. Noteworthy, children with HIV infection and concurrent SLE usually develop manifestations of renal disease, such as focal glomerulosclerosis, mesangial hyperplasia, and LN. [4,5] Such result is consistent with the recent findings that earlier onset of SLE may involve more renal features. [10] However, the etiology of renal involvement in cases with coexisting SLE and HIV is difficult to determine. Renal complications due to HIV are also diverse. [11] Without a definitive etiology, therapy in such patients is extremely difficult. Six deaths have been reported, all of which were in infected cases and cases of HIV diagnosed before the age of 10 years, except for 1 congenitally infected child without follow-up. The diseased children >10 years were all reported to remain stable or show improvement of HIV infection and SLE conditions under antiretroviral therapy (ART) and a lupus-based regimen (chloroquine [CQ], corticosteroids [CS], hydroxychloroquine [HCQ], and/or mycophenolate [MMF]). According to these results, it seems that earlier onset of SLE and HIV infection is fatal. Twenty-one adult patients developed SLE after HIV infection, [6,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] with the age at HIV diagnosis ranging from 23 to 47 years (median, 38 years). Most adult patients (16/21, 80.0%) were females, in accordance with the reported frequency ratio of 4.3-9:1 (female-to-male ratio). [27,28] The CD4 T-cell count at the time of SLE diagnosis was <500 cells/mm 3 in 15 patients and >500 cells/mm 3 in 2 patients, and was not reported in 4 patients. Clinical manifestations included respiratory distress, neuropathy, abnormal laboratory findings, and other associated symptoms. These patients were reported to respond well to treatment with CQ, and oral CS with or without HCQ. A simultaneous ART also helped them control the HIV infection, as all the patients reported improved or stable HIV infection. Hence, none of them were reported dead and most of them achieved partial, if not complete, remission.
Thirty-two patients died of SLE followed by HIV infection. [6,16, The age of SLE diagnosis ranged from 18 to 55 years (median, 30 years), while most patients (26/32, 81.2%) were females, consistent with the known female predominance of SLE incidence. The duration of SLE before the diagnosis of HIV infection ranged from 2 weeks to 204 months (median duration, 72 months). Eighteen patients received ART, 10 did not, and 4 had no available information on ART. The patients were treated with SLE therapy, including CS, CQ, HCQ, CYC, and/or MMF, except for 2 patients who lacked the pertinent information, and most of them exhibited inactive SLE after the onset of HIV infection regardless of the use of ART. One patient developed a lupus flare 7 months after ART [30] . One patient developed LN 13 months after ART. [50] Two patients progressed to end-stage renal disease. [6,48] Seven died of acquired immunodeficiency syndrome (AIDS)-related infection, despite 3 of them receiving ART. Two of them were diagnosed as having HIV infection after death.
We also identified 10 cases featured by a simultaneous diagnosis of SLE and HIV during the same admission. [14,16,[51][52][53] However, the precise timing of onset of either condition is difficult to ascertain for some patients considering the long duration between seroconversion and diagnosis of HIV infection in some patients. [54] The age at diagnosis ranged from 18 to 44 years (median, 26 years). Again, female was the predominant sex in this group (8/10, 80%). Three patients were not receiving ART before and after diagnosis, among which 1 died of meningitis infection [53] and the other 2 developed lupus flare after months. [14] The rest of the patients tolerated ART and exhibited inactive or improved SLE and HIV, except that 1 patient who initially had inactive SLE developed flare after receiving ART for 82 months. [14] 4. Discussion and conclusion Zhang et al reported a seminal study on the spectrum and characteristics of rheumatic complications in HIV patients in China and described 1 HIV-infected patient presenting with lupus-like syndrome. [55] However, it is unknown whether this fulfills the American College of Rheumatology or the SLICC criteria for SLE diagnosis. Herein, we present the first concurrent case of SLE and HIV infection in China. The diagnosis is achieved by combination of the clinical presentation, laboratory findings, and medical history. Interestingly, the diagnosis was more coincidental than a result of stringent reasoning. The accurate times of the onsets of SLE and HIV infection were also unknown. He was referred to our hospital again because he caught a cold and regained the symptoms. Therefore, he was likely to be infected with HIV infection after hospital discharge, that is, he developed HIV infection with a SLE history. During hospitalization, a renal biopsy was not executed considering the low platelet count, which may have been resulted from HIV-associated immune thrombocytopenic purpura or the side effect of cyclophosphamide. As long as the coexistence is confirmed, therapeutic intervention is required, considering that a immunosuppressant dose is crucial to the pathogenesis of AIDS disease progression. This patient was referred to the CDC to control the HIV infection via ART first and keeps a routine monitoring of CD4 T-cell count and HIV VL. Accordingly, he was given SLE therapy. Under such management, he remained stable in terms of both HIV infection and SLE until the recent follow-up.
Since the first case reported in 1988, [31] only a few cases of concurrent SLE and HIV infection have been reported. Sporadic reported concurrent cases have attracted increasing attention to the potential association of SLE and HIV infection. In fact, these 2 conditions share multiple overlapping clinical features, including hematological, neurological, renal, and other abnormalities. Presentations with lymphopenia, hemolytic anemia, or thrombocytopenia are common in both disease sets. Both may display manifestations that include psychosis, peripheral neuropathy, and focal deficits. Nephropathy is another common manifestation of both diseases. [6,56] Nonspecific symptoms of such wide range make great challenges to the diagnosis of concurrent cases and differential diagnosis of cases with mimicking clinical manifestations.
Overproduction of ANAs and anti-dsDNA antibodies is a hallmark of SLE. ANAs are of diagnostic, pathological, and prognostic significance during lupus disease course. Noteworthy, recent studies revealed polyreactivity or autoreactivity one of the key features of anti-HIV antibodies, especially antibodies with broad and potent neutralizing abilities. [57][58][59] Although existing in low titer, these ANAs resulted from disrupted immunological milieu may play an etiological role in autoimmune diseases. Furthermore, patients with SLE may also produce antibodies cross-reacting with HIV antigens, therefore leading to false positive tests for HIV infection. [60][61][62][63][64] HIV-infected individuals may also produce autoantibodies, such as ANAs and anticardiolipin antibodies, [58,65] causing diagnostic difficulties.
Although the concomitant cases of SLE and HIV infection are limited, the isolated coexisting cases indicate that these 2 conditions are not mutually exclusive. As HIV is gradually affecting more heterosexual populations than homosexual men and female predominates in populations with lupus, more cases may be reported in the future. Therefore, elucidation of the underlying disease mechanisms and timely diagnosis should provide a better understanding of the pathogenesis, new therapeutic strategies, and improved care of patients. Laboratory technicians and clinicians should combine the results of western blot, PCR analysis, and CD4 T-cell count to exclude falsepositive result for HIV infection concurrent with SLE onset. For SLE patients with confirmed HIV infection, anti-HIV therapy should be considered before immunosuppressive treatment. Moreover, monitoring of CD4 T-cell count is strongly recommended in terms of determining the appropriate immunosuppressant dose.