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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 126-130

The effect of human immunodeficiency virus on functional recovery in hospitalized patients with stroke


1 Department of Rehabilitation Medicine, School of Medicine, Emory University, Atlanta, GA, USA
2 Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA

Date of Submission16-Mar-2020
Date of Decision24-Jul-2020
Date of Acceptance27-Jul-2020
Date of Web Publication09-Oct-2020

Correspondence Address:
Dr. David T Burke
Department of Rehabilitation Medicine, School of Medicine, Emory University, 12 Executive Park NE, Atlanta, GA 30329
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jisprm.jisprm_24_20

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  Abstract 


Background and Objective: Given the known association between inflammatory conditions and stroke, this study was designed to assess whether the diagnosis of human immunodeficiency virus (HIV) – which is associated with chronic inflammation – would affect the functional trajectory of patients hospitalized for the treatment of stroke. Methods: This is a retrospective study comparing the functional outcomes of 688,066 stroke patients with a diagnosis of HIV to those without a diagnosis of HIV from 2002 to 2017. Results: HIV+ patients were found to have a much lower age at admission, with a difference of over 10 years when compared to HIV− patients. HIV+ patients were also less likely to discharge to home when compared to HIV− patients (P < 0.0001). Gains in functional independence measure (FIM) scores per day were found to be greater among those who were HIV− compared to those who were HIV+ (P = 0.086). Factors associated with a lower FIM efficiency included older age at admission, male gender, and having a hemorrhagic stroke (P < 0.0001). Conclusion: This study found that, among those hospitalized for the treatment of a stroke, the functional gain per day was inferior among those with HIV than among those without HIV at admission.

Keywords: Functional independence measure, human immunodeficiency virus, inflammation, rehabilitation outcomes, stroke


How to cite this article:
Burke DT, Pullen S, Bell RB, McCargo T, Tian G. The effect of human immunodeficiency virus on functional recovery in hospitalized patients with stroke. J Int Soc Phys Rehabil Med 2020;3:126-30

How to cite this URL:
Burke DT, Pullen S, Bell RB, McCargo T, Tian G. The effect of human immunodeficiency virus on functional recovery in hospitalized patients with stroke. J Int Soc Phys Rehabil Med [serial online] 2020 [cited 2020 Dec 3];3:126-30. Available from: https://www.jisprm.org/text.asp?2020/3/4/126/297641




  Introduction Top


In 2017, 36.9 million people worldwide were living with human immunodeficiency virus (HIV).[1] Over the past 30 years, the development of antiretroviral therapy (ART) has drastically extended the lifespan and reduced the incidence of comorbidities among people living with HIV (PLHIV). Without ART treatment, PLHIV will experience progressive immunodeficiency with opportunistic illnesses, leading to acquired immunodeficiency syndrome (AIDS). However, with proper treatment, PLHIV can anticipate a life expectancy similar to their HIV− counterparts.[2] Improvements in treatment have facilitated many PLHIV to attain an undetectable viral load within 12 weeks after beginning treatment, and have led to the emergence of a new and growing population of aging PLHIV.[2],[3]

Even with appropriate treatment, however, evidence suggests that PLHIV are at a greater risk of non-AIDS-related morbidity and mortality than are those without HIV.[4],[5],[6] Among these are neurocognitive disease, osteoporosis, liver disease, kidney disease, and some cancers. Research suggests that PLHIV are at risk for developing cardiovascular disease (CVD) at a younger age and have an increased risk of ischemic stroke, heart failure, and peripheral artery disease.[5],[6]

Several factors contribute to this excess risk including antiretroviral drug toxicity, a high prevalence of traditional risk factors (such as substance abuse, obesity, and hypertension), immune dysfunction, and inflammation. After decades of research, it is clear that HIV infection is now a chronic inflammatory disease and that the disease shares a remarkable similarity to a number of other inflammatory noninfectious diseases. This persistent inflammatory and/or hypercoagulable state may, in some people, persist indefinitely, even as HIV replication is largely controlled by ART.[4]

Given the unique risk factors in this population, the authors believe that HIV+ patients will recover less efficiently than HIV− patients.


  Methods Top


A retrospective review was conducted after receiving institutional review board approval. The study included consecutive patients admitted to an acute rehabilitation hospital after a diagnosis of acute stroke from 2002 to 2017. It is unknown if the admission was the first diagnosis of stroke and during this time period, there was no significant change in the treatment options available to those living with HIV. During this time, there was no significant change in the treatment options available to those with HIV [Table 1]. The data were recorded in eRehabData®, which includes data from 518 participating inpatient rehabilitation facilities (IRFs) in the USA. eRehabData® is an online patient assessment system offered by the American Medical Rehabilitation Providers Association to assist IRFs with the Centers for Medicare and Medicaid Services guidelines. All patients were admitted to the IRF immediately after stabilization in the referring acute care hospital. The data include demographic information, the hospital length of stay (LOS), and the functional independence measure (FIM) scores. The FIM is a well-established and uniform system of measurement for disability based on the International Classification of Impairment, Disabilities, and Handicaps for use in the medical system in the USA. The FIM score was used to measure the level of each patient's disability, which thus indicates the amount of support needed to care for them upon discharge, as items are scored on the basis of how much assistance is required for care. Using these data, those with a diagnosis of HIV were compared to those without HIV for changes in FIM per day and LOS. For continuous variables, two-sample t-test was used to compare the means between HIV+/HIV− groups; for categorical variables, Chi-square test was used to test the association of the categorical variable and the HIV diagnosis status. To evaluate the association between the discharge status and other variables, a logistic regression model was fit using the discharge status as the outcome and other variables as the covariates, and the final model was chosen based on forward model selection (significance of entry = 0.05). Similarly, to evaluate the association between FIM efficiency and other variables, a multiple linear regression model was fit using FIM efficiency as the outcome and other variables as the covariates, and the final model was chosen based on forward model selection (significance of entry = 0.05). Statistical analyses and data cleaning were performed using SAS® software, version 9.4 (Cary, NC, USA) version 9.4 and IBM's SPSS Statistics, version 24 (Cary, NC, USA). Statistical hypothesis tests with P < 0.05 were considered statistically significant.
Table 1: Baseline characteristics

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  Results Top


Through the chart review, we identified 688,006 patients with an ICD-9 or ICD-10 diagnosis of stroke. These included 577,908 ischemic strokes and 96,783 hemorrhagic strokes [Table 1]. Of these, 685,966 (99.7%) were HIV− and 2040 (0.3%) patients were HIV+. Of the total admissions, 335,832 (49%) were male, with an average age at admission of 69.25 years. Hypertension was found in 64% of HIV+ and 58% of HIV− patients. The prevalence of diabetes (4%) and overweight/obesity (8%, 9%) was found to be similar for both groups.

By stroke subtype, hemorrhagic stroke was found in 14% of the HIV− and 15% of the HIV+ participants. Ischemic stroke was found in 84% of the HIV− and 82% of the HIV+ participants. Of those who were HIV−, 49% were male, whereas of those who were HIV+, 70% were male. The mean age at admission of those HIV− participants was 69.3 years and of those HIV+ was 51.39 years. The median discharge FIM scores were 84 for HIV− patients and 87 for HIV+ patients.

On unadjusted analysis, reviewing the FIM gains while in the IRF, the FIM change per day (FIM efficiency) of those HIV− was 1.50 and for those HIV+ was 1.55 (P = 0.469). In this analysis, the mean LOS was 16.54 days for those HIV− and 17.18 for those HIV+ (P = 0.086). In addition, both HIV− and HIV+ patients were likely to be discharged home (61%, 64%), as shown in [Table 1].

After completing a logistic regression, discharge to home was less likely among those who were HIV+ as compared to the HIV− (odds ratio [OR] = 0.6987, P < 0.0001), as well as those who were older (OR = 0.9812, P < 0.0001) [Table 2]. In the same analysis, factors associated with a greater likelihood of discharge to home included higher FIM score at discharge (OR = 1.0192, P < 0.0001) and longer LOS (OR = 1.0067, P < 0.0001). Controlling for age at admission, stroke type, and gender, FIM efficiency was worse among those who were HIV+ as compared to those who were HIV− (P < 0.0001) [Table 3]. Other factors associated with a lower FIM efficiency included older age at admission (P < 0.0001), male gender (P < 0.0001), and hemorrhagic stroke (P < 0.0001). The lower FIM efficiency among HIV+ group can be explained by the significantly different age distribution among HIV+ and HIV− groups.
Table 2: Discharge to home

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Table 3: Functional independence measure efficiency outcome

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After running the multiple linear regression [Table 4], those factors that were independently associated with a worse FIM efficiency included being HIV+, older aged at admission, male gender, having a hemorrhagic stroke, and having a history of cardiac arrest as well as diabetes mellitus. Improved FIM efficiency was associated with hypertensive disease and an elevated body mass index [Table 4].
Table 4: Multiple linear regression: Functional independence measure's efficiency and risk factors

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  Discussion Top


Emerging evidence suggests that certain HIV-related risk factors, including inflammatory conditions, may elevate the risk of stroke. Despite this, stroke is a relatively overlooked aspect of HIV-related risks. This study focused on the functional recovery of patients hospitalized for the treatment of an acute stroke. We chose this setting as this enabled us to use the tools of measured functional outcome common in the acute setting (FIM), with the repeated FIM scores addressing an array of motor and cognitive skills. With a focus on stroke, and given the association between inflammation and stroke, we anticipated that the HIV diagnosis, now one of the chronic inflammations, would result in strokes occurring at an earlier age and adversely affect the outcome of these patients during hospitalization. We found this to be true.

During acute HIV infection, the immune system is highly activated. Inflammatory markers appear to directly correlate with morbidity and mortality in patients infected with HIV. Microbial translocation, low-grade viremia, co-infection, and adverse events from combination ART all contribute to chronic inflammation and T-cell activation.[5] As the infection proceeds to the chronic phase, the inflammatory response is not resolved. This leads to a state of chronic immune activation thought to be central to a number of comorbidities.

We anticipated, therefore, that this chronic inflammatory state would affect the trajectory of patients admitted for stroke. As we had projected, those who were admitted with a diagnosis of HIV demonstrated a reduced rate of functional recovery per hospital day as compared to those who were HIV−. Further, those who were HIV+ were less likely to be discharged to home as compared to those without a diagnosis of HIV. Given these results, our data suggest that after a stroke, recovery will be slower and less likely to result in the desired outcome after at the time of discharge to home. These findings seem to reflect that systemic inflammation, evident at the time of stroke occurrence, has found impaired outcomes of both death and disability.[6] A 2018 study that compared stroke recovery between HIV+ and HIV− patients in an inpatient rehabilitation clinic (n = 141), found no statistically significant differences in functional abilities between the two groups at admission and discharge.[7] This study did not report on significant comorbidities.[7]

In a study involving 844 patients with ischemic stroke, the OR for association of inflammatory markers with poor outcome following a stroke was 3.1 for elevated interleukin-6 and 1.9 for elevated C-reactive protein (CRP).[6] Systemic inflammation amplifies an inflammatory reaction in the brain and consequent neuronal damage, and can also be a catalyst for immune system decline.[5],[8] Data show that most stroke patients present with comorbidities including atherosclerosis, hypertension, diabetes, and/or infection.[9] A common feature of these conditions is an elevation in the systemic inflammatory response. Indices of these included raised circulating levels of CRP and elevated leukocyte count, both found to be predictive of strokes. While not demonstrating causality, these findings do support a link between systemic inflammation and stroke susceptibility.[10] Those who have studied atherothrombosis, the leading cause of stroke, recognize inflammation as central to the initiation, development, and rupture of the atherosclerotic plaques.[11] Beyond vascular inflammation, some have demonstrated that nonvascular peripheral inflammatory events may modify stroke susceptibility.[12],[13] Even acute bacterial infections have been shown to increase this risk.[9] Chronic diseases, such as periodontitis that result in a low-grade systemic inflammation, are also thought to be predisposing factors for stroke.[14],[15],[16] Potential contributors to the risk of stroke in HIV+ patients may also include opportunistic infections, tumors, atherosclerosis, diabetes, hypertension, autoimmunity, coagulopathies, CVD, and direct infection of the arterial wall by HIV.[17],[18]

In addition to risk factors for stroke onset, other studies have indicated that inflammatory conditions are risk factors for recovery after a stroke.[6],[19] Further, studies have shown a negative correlation between inflammatory markers and measures of function after a stroke.[20],[21],[22] Given these data, it was not a surprise that, among those hospitalized for treatment of a stroke, compared to the HIV−, those who were HIV+ had a slower and inferior recovery during the acute stroke process.

In this study, HIV+ patients had a much-reduced age at admission. This is consistent with evidence pointing to reduced age for adverse cardiovascular events among PLHIV compared to their HIV− peers.[23] Given the younger age at admission among PLHIV, surveillance of PHIV for cerebrovascular risk factors seems warranted. Regular screening for and diligence among the primary providers may detect manifestations of cerebrovascular disease may present earlier than would the general population.

Limitations

It is beyond the scope of this publication to assess whether this difference in age at admission is a real phenomenon, as we did not review the data of those presenting to the acute care facilities. It may be that those with HIV were not referred to the IRF facility at the same rate as those without.

Studies have shown that admission to an IRF can be influenced by factors such as insurance status and sociodemographic factors, which were not well explored in this study. As a population, those with HIV are less likely to have insurance coverage than are those without HIV: nearly 30% of PLHIV are uninsured, compared to 8.8% of uninsured people in the general population without coverage.[12],[24] As such, those admitted to our facilities may represent a skewed population, which do not reflect the potential trajectories of all those with HIV. To better understand this, future studies should include all patients admitted to acute care facilities for treatment of stroke as well as prospective population studies following those with and comparing them to those without a diagnosis of HIV.

Currently, several drugs are available that influence the effects of systemic inflammation, including platelet aggregation inhibitors, lipid-lowering agents, fibrates, β-adrenoreceptor antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and antidiabetic drugs.[25] We did not include these medications in our analysis. Future study may help understand how these might uniquely influence the comorbidities of PLHIV.


  Conclusions Top


We believe ours to be the first study to examine the effect of HIV infection on functional outcome measures among people diagnosed with an acute stroke and admitted to an IRF. We found that the diagnosis of HIV is associated with a slower gain per day in functional scores (FIM) while in a rehabilitation hospital. Due to increased life expectancy for PLHIV, it can be anticipated that rehabilitation facilities will see increased admissions of PLHIV resulting from a combination of traditional cardiovascular risk factors and/or HIV-related inflammation.

Financial support and sponsorship

Statistics was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflicts of interest

There are no conflicts of interest.



 
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