Recurrent skin and soft tissue infections in HIV-infected patients during a 5-year period: incidence and risk factors in a retrospective cohort study

In 1998, the first increase in incidence of methicillin resistant Staphylococcus aureus (MRSA) infections in people without previous contact with the health care system was reported in children in Chicago [1]. Community-associated (CA-MRSA) infections were subsequently identified in other groups in the United States, especially marginalized populations, and CA-MRSA quickly became the leading cause of skin and soft tissue infections (SSTIs) with community onset among incarcerated populations and among impoverished urban populations [2, 3]. The advent of the CA-MRSA era dramatically affected the epidemiology of SSTIs, with a doubling in the number of SSTIs seen at safety net hospital emergency rooms [2].

Patients with human immunodeficiency virus (HIV) infection are particularly prone to infection with CA-MRSA because they are immunocompromised and because of demographic, behavioral, and socioeconomic factors as well as frequent exposures to the health care system [4, 5]. We have recently evaluated risk factors for a first SSTI among 511 HIV-infected patients in Chicago [6]. In that study, accounting for follow-up time, chronic skin conditions such as psoriasis and lymphedema, presence of an intravenous catheter, and lack of virologic suppression were most strongly associated with initial SSTI occurrence. There was also a trend toward an increased risk of SSTI in subjects receiving health insurance through Medicaid, the governmental health insurance program for the poor and disabled, and subjects with sexually transmitted diseases (STDs). Other studies have identified different risk factors [4], though our study differed methodologically from many other studies in that we identified all SSTIs which were documented in the medical record, not just SSTIs which were culture positive for S. aureus. This is important because in our study we found that cultures were more likely to be sent during an SSTI episode in patients with advanced immunocompromise [6]. Therefore, relying on culture data as a criterion for detection of an SSTI in retrospective studies may lead to biased conclusions about the epidemiology of SSTIs in the HIV-infected population. Although a number of anecdotal reports have suggested that recurrent SSTIs are common among HIV-infected patients [7, 8], few studies have examined the incidence of and risk factors for recurrent SSTIs in the HIV-infected population in the current era of CA-MRSA [9‐12]. Accordingly, we set out to examine the risk factors for SSTI recurrence in an HIV-infected population receiving care at an urban tertiary care center clinic in the CA-MRSA era.

In an urban, primarily African-American cohort, we confirmed that patients infected with HIV who had a medically attended SSTI had a high rate of subsequent SSTI, with most recurrences diagnosed within months of the initial SSTI. We identified risk factors for recurrence which do not entirely overlap the risk factors for initial SSTI found in our previous paper [19] or in the work of others [20], though our studies differed from most other studies in examining all subjects with SSTIs, not just those with proven MRSA SSTIs. It may be that the risk factors for initial SSTI occurrence differ from those that predispose to continued colonization with or re-exposure to pathogenic bacteria.

In our cohort, African Americans, who constituted more than 90 % of the patient sample, demonstrated a significantly lower rate of recurrent SSTI as compared with others. We surmise that the risk factors leading to initial SSTIs in those not of African-American descent in our cohort may be more strongly associated with the risk of SSTI recurrence than the risk factors leading to initial SSTI in African Americans. However, our sample of non-African Americans is too small to permit rigorous testing of this hypothesis. Previous observational cohorts have noted that African-Americans are less likely to remain in care [21], but differential rates of follow-up for African-Americans would only explain our results if African Americans having recurrent SSTIs were more likely than other African Americans to be lost to follow-up. We also found that established risk factors for SSTI recurrence such as intravenous drug use and presence of an intravenous catheter [8] predicted SSTI recurrence.

Some of our preliminary modelling suggested an independent impact of a gonorrhea diagnosis, although the STD incidence observed in our population was too low to assess reliably the effect of STD diagnosis on SSTI recurrence risk. It has been proposed that ongoing high risk sexual behavior may re-expose HIV-infected patients to pathogenic strains of MRSA. Prior studies by other researchers have found that many HIV-infected patients only demonstrate groin colonization with MRSA without colonization at other sites [22]. The occurrence of gonorrhea or other STDs may serve as a marker of continuing exposure to other colonized individuals, leading to reacquisition of pathogenic strains and predisposing towards SSTI recurrence.

We found that non-hepatitis liver disease, which in our cohort was predominantly due to alcoholic liver disease, was a risk factor for recurrent SSTI. Although not previously described specifically as a risk factor for recurrent SSTI in HIV-infected populations, the association between cirrhosis and SSTI risk has been previously described by other authors [23].

We were unable to test the finding of others that treatment of the initial SSTI with minocycline reduces the risk of recurrence [11] because only one patient in our study received minocycline as the treatment for the initial SSTI, which reflects institutional preferences for certain antimicrobials for the treatment of SSTIs at our center.

Our finding that lack of virologic control, better than CD4+ lymphocyte count per se, predicted SSTI risk is difficult to explain but is consistent with the findings of other authors [10]. This effect may be related to the immunologic effect of uncontrolled HIV replication. Alternatively, unsuppressed viral load, a marker of poor adherence to medication, may serve as a marker of patients who are not taking trimethoprim-sulfamethoxazole prophylaxis to prevent pneumocystis pneumonia, which potentially may also be protective against SSTI [24, 25]. Alternatively, lack of virologic suppression may be a marker of other behavioral and demographic risk factors for SSTI.

Our study is one of only six in which authors have examined SSTI recurrence in HIV-infected adults (Table 4). Skiest et al. performed a single-center prospective study at an urban, public clinic in Dallas, accruing patients with initial S. aureus skin infection seeking outpatient care in 2003–2004 [12]. Recurrent SSTI was noted in 11/37 patients (29.7 %). Adjustment for variable length of follow-up after the initial SSTI was not performed. Whether or not appropriate antimicrobial therapy was prescribed and whether or not incision and drainage was performed did not affect recurrence risk. No additional statistical analysis of risk factors for recurrence was reported.

Graber et al. performed a single-center retrospective study at an urban, public clinic in San Francisco, accruing patients with initial MRSA infection seeking outpatient care in 2002–2006 [9]. Patients were followed through 2007. A recurrent SSTI occurred in 44/62 patients (71.0 %). Adjustment for variable length of follow-up after the initial SSTI was not performed. The median time to recurrence was 135.5 days, which was similar to the finding in our study. Cox regression performed on demographic and clinical predictors did not yield a significant predictor of SSTI recurrence. Of 62 patients with an initial MRSA SSTI, 17 (27 %) developed a recurrence.

Vyas et al. performed a single-center retrospective study at a military-affiliated HIV clinic in San Diego, accruing patients with initial MRSA SSTI in 2003–2010 [7, 11]. Patients were followed through 2010. Of 63 patients with initial MRSA SSTI, 17 (27 %) experienced a recurrent MRSA SSTI. Adjustment for variable length of follow-up after the initial SSTI was not performed. The lower rate of recurrence in this study may have resulted from the inclusion of only culture-proven recurrences. Incision and drainage was not associated with a decreased risk of recurrence. Use of an antibiotic other than minocycline and hospitalization for the initial SSTI were significant risk factors for recurrence in a multivariable analysis (Table 4). Patients with a recurrent SSTI demonstrated a significantly lower CD4+ count in a mixed-effects model using CD4+ lymphocyte count as the outcome.

Crum-Cianflone et al. performed a single-center retrospective study at a military-affiliated HIV clinic in San Diego, accruing patients with initial MRSA SSTI in 2000–2007 [10]. This study was performed at the same center as Vyas’s study in an overlapping time frame. Of 31 patients with initial MRSA SSTI, 14 (41 %) had a recurrent SSTI. The proportion of recurrence in this study differed from that observed in the Vyas study as the outcome included all SSTIs, not just SSTIs proven to be caused by MRSA. Median time to recurrence was 4 months, comparable to the results of our study. In a multivariable logistic regression model, only HIV VL > 1000 copies/mL was a significant predictor of recurrence.

Crum-Cianflone et al. examined data from the US Military HIV Natural History Study, a multicenter prospective cohort study, from 2006 to 2010 [26]. Of 379 subjects with an initial SSTI, 31 % experienced a recurrence at a median 7 months after the initial SSTI. They did not identify a statistically significant risk factor for recurrent SSTI. However, there was some suggestion in the data that the presence of a dermatological condition at the time of diagnosis of the initial SSTI (HR 1.99; 95 % CI 0.95–4.16; p = 0.07) and higher HIV RNA level (HR 1.18 per 10-fold increase in viral load; 95 % CI 0.98–1.43; p = 0.08) may have been associated with recurrence.

Our study was limited as it was a single-center retrospective medical record review. Therefore, some demographic information was missing. The diagnosis and outcome of SSTI was based on physician documentation. Older paper records were incomplete. SSTIs diagnosed at centers other than our own were missed, and so our estimate of SSTI recurrence risk was likely a lower bound. We have no specific data on how often patients in our cohort sought care elsewhere. There are community hospitals with emergency departments but no other major tertiary care centers within five miles of our center. Cox regression requires an assumption of non-informative censoring (i.e., that subjects who are lost to follow-up are similar in their characteristics to those who remain engaged in care), and the results of our analysis may be biased to the extent that this assumption is violated. However, the problem of loss to follow-up is inherent to any study of urban HIV-infected populations [27].