|Year : 2018 | Volume
| Issue : 2 | Page : 45-51
Effect of CD4 T-lymphocyte count and human immunodeficiency virus (HIV) infection stage on the prevalence and pattern of rheumatologic disease in HIV-infected patients in Zaria, North-Western Nigeria
AbdulAziz Umar1, Olufemi O Adelowo2, Sani B Garko1
1 Department of Medicine, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
2 Department of Medicine, Lagos State University Teaching Hospital, Lagos, Nigeria
|Date of Web Publication||1-Nov-2018|
Department of Medicine, Ahmadu Bello University Teaching Hospital, PMB 06, Shika, Zaria, Kaduna State
Introduction Human immunodeficiency virus (HIV) infection is a scourge of the modern time. Occurring with high frequency in patients of all ages and both genders, and across all strata of the society, HIV being a systemic disease can affect the musculoskeletal system, and therefore, musculoskeletal disease maybe a presenting symptom of HIV infection. There is paucity of research on the effect of different stages of HIV and CD4 T-lymphocyte count on HIV rheumatological manifestations among Nigerian patients. This study aims at evaluating the effect of CD4 T-lymphocyte count and the stages of HIV on the prevalence and pattern of rheumatological disease in Nigerian patients with HIV infection.
Objective To determine the effect of CD4 T-lymphocyte count and HIV stage on the occurrence and pattern of rheumatologic diseases among patients attending HIV clinic at Ahmadu Bello University Teaching Hospital, Zaria.
Materials and Methods Between February 2011 and March 2012, 200 HIV-seropositive patients [consisting of 100 patients on combined antiretroviral therapy (cART) and 100 cART naïve patients] and 200 age and gender-matched HIV-negative controls were screened for the presence of rheumatologic disease, using a validated interviewer administered questionnaire. Information gathered on patients included sociodemographic characteristics, risk factors for HIV infection, clinical and laboratory parameters. CD4 T-lymphocyte of HIV patients and controls were quantified using flow cytometry method. CD4 categorization of patients was performed using the Centre for Disease Control Criteria, and HIV staging was done using World Health Organization criteria. Those with rheumatologic diseases were diagnosed using the American College of Rheumatology classification criteria or, where not available, other well validated rheumatological classification criteria. Data obtained were analyzed using Statistical Package for Social Sciences window software version 17.0. A P value of <0.05 was used as level of significance.
Results Rheumatological disease was diagnosed in 56 (28%) of HIV-positive patients and 15 (7.5%) of HIV-negative control. The odd ratio for occurrence of rheumatologic disease in HIV-positive patients compared to control was 4.8 [95% confidence interval (CI) = 2.61–8.82, P = 0.001]. In 3% of HIV infected patients, rheumatologic disease was the reason for their 1st presentation. The spectrum of rheumatic disease seen in HIV-positive patients is as follows: HIV-associated polyarthritis in 13 (16.5%) patients, polyarthralgia in 10 (5%) patients, undifferentiated spondyloarthropathy and reactive arthritis in nine (4.5%) patients each, septic arthritis in five (2.5%), and Tuberculosis (TB) of the spine and pyomyositis in three (1.5%) patients each. CD4 T-lymphocyte count and HIV stages were independent determinants of HIV-associated rheumatologic disease.
Conclusion Rheumatologic diseases occur more frequently in HIV-seropositive patients compared to HIV-negative controls, and low CD4 T-lymphocyte counts and advanced HIV stage are associated with higher prevalence of rheumatologic diseases.
|How to cite this article:|
Umar A, Adelowo OO, Garko SB. Effect of CD4 T-lymphocyte count and human immunodeficiency virus (HIV) infection stage on the prevalence and pattern of rheumatologic disease in HIV-infected patients in Zaria, North-Western Nigeria. Sub-Saharan Afr J Med 2018;5:45-51
|How to cite this URL:|
Umar A, Adelowo OO, Garko SB. Effect of CD4 T-lymphocyte count and human immunodeficiency virus (HIV) infection stage on the prevalence and pattern of rheumatologic disease in HIV-infected patients in Zaria, North-Western Nigeria. Sub-Saharan Afr J Med [serial online] 2018 [cited 2019 Jan 16];5:45-51. Available from: http://www.ssajm.org/text.asp?2018/5/2/45/243935
| Introduction|| |
Human immunodeficiency virus (HIV) causes a multisystemic disease, and consequently, the musculoskeletal system is often affected. A wide spectrum of rheumatological conditions has been described in HIV patients, some of which include arthralgia, psoriatic arthritis, reactive arthritis, HIV-associated arthritis (HIVAA), myalgia, myositis, rhabdomyolysis, painful articular syndrome, septic arthritis, fibromyalgia, vasculitides, etc.,,,,
The prevalence of musculoskeletal disease in patients with HIV varies between 11% and 30%,, depending on the study methodology, route of HIV acquisition, stage of the disease, and ARV treatment status. Rheumatologic manifestation can occur in the setting of early or late HIV disease.
In African patients, HIV infection has resulted in both increased incidence and alteration of pattern of rheumatological diseases. Prior to the advent of HIV infection, the incidence and prevalence of spondyloarthropathy was noted to be low in Africans due to low population prevalence of the predisposing HLA B27 gene in Africans (0.5%–1%) compared to Caucasians (5%–10%). Moreover, in some African countries, between 72% and 90% of spondyloarthropathy patients were noted to be HIV positive.,
Rheumatologic disease can occur at any stage of HIV infection. Although studies have alluded to the predominant occurrence of rheumatologic manifestation in late stages of HIV disease, they can also occur in early HIV disease and can occasionally be the prime symptom of HIV.
Of the several factors that have been noted to affect the occurrence of rheumatological disease in the setting of HIV infection, perhaps the most important is the CD4 T-lymphocyte and by extension, the HIV stage. CD4 T-lymphocyte has been shown to be a predictor of HIVAA. HIV-induced CD4 T-lymphocyte cell depletion affects the manifestation of rheumatic disease in several ways, namely, increased overall prevalence of rheumatologic disease, changing pattern of HIV-associated rheumatic disease, and increased severity of individual rheumatic disease.,
With decline in CD4 count to below 500 cells/μL and progression in HIV stage, the pattern of rheumatic disease tends to change among population of HIV patients. Immune complex diseases and vasculitis tend to be predominant at CD4 levels of 200 to 499 cells/μL. As CD4 count drops to below 200 in association with reversal of CD4:CD8 T-lymphocyte ratio, spondyloarthropathic diseases such as reactive arthritis, undifferentiated spondyloarthropathy, and psoriatic arthritis tend to predominate. Infective conditions such as pyomyositis, osteomyelitis, and septic arthritis predominantly occur in advanced HIV, when the CD4 count is generally less than 200 cells/μL, and often below 100 cells/μL.
The increased occurrence of rheumatologic diseases in the setting of HIV infection is associated with a decreased health-related quality of life, loss of employment, and loss of self-care in affected patients. HIV-associated rheumatologic disease can also be associated with increased mortality.
Thediagnosis and treatment of HIV-associated rheumatologic diseases poses management challenge, given the likelihood of usage of potentially immunosuppressing disease modifying antirheumatic drugs and immune biologics in the setting of an immunosuppressive disease, with the possibility of heightened risk of opportunistic infections and rapid progression to advanced HIV (AIDS).
There is a paucity of research on the impact of CD4 T-lymphocyte count and HIV disease stage on the prevalence and pattern of rheumatological diseases in Nigerian patients infected with HIV. Hence, this study was conducted to fill this void in knowledge.
| Materials and methods|| |
Study population and study design
The study was a case–control cross-sectional study comprising 200 HIV-positive patients [consisting of 100 patients on combined antiretroviral therapy (cART) and 100 cART naïve patients] and 200 HIV-negative control. HIV-positive patients were recruited from the HIV clinics, medical wards, voluntary counseling and testing (VCT) center, and blood donation center of Ahmadu Bello University Teaching Hospital (ABUTH), Zaria, from February 2011 to March 2012. Age and gender-matched HIV-negative controls were recruited from HIV-negative patients at the VCT center, blood donation center, and from HIV-negative relatives of HIV-positive patients.
A validated researcher-administered questionnaire was used to screen for rheumatologic disease in HIV-positive patients and HIV-negative controls. Rheumatologic disease in patients and controls was diagnosed using American College of Rheumatology Criteria or other relevant diagnostic criteria. For HIV-positive patients, additional information ascertained included period of HIV diagnosis and risk factor for HIV infection ARV status (naïve or experienced); the duration of ARV, past, and current types of ARV regime was ascertained and confirmed from the HIV clinic database. World Health Organization (WHO) clinical staging of HIV patients was used in the staging of all HIV-positive patients. Patients with post-traumatic arthritis, degenerative arthritis, Hepatitis B and C virus positivity, and moribund HIV patients were excluded from the study.
HIV status in all HIV-positive patients was confirmed by western blot technique. HIV-negative patients were screened using rapid HIV screening kit, and discordant results were resolved by a third kit (tie breaker). Three kits (STAT-PAK, Chembio Diagnostics Systems Inc., USA; Determine, Alere Medical Comp Ltd, Japan; and Uni-Gold, Trinity Biotech Plc, Ireland) were used according to manufacturer’s instruction. CD4 T-lymphocyte count was done for both patients and control by flow cytometry method using Cyflow SL (Partec, Munster, Germany). CD4 T-lymphocyte count was used to subcategorize HIV-positive patients based on Centre for Disease Control classification scheme. Where indicated, patients underwent radiographic evaluation, Mantoux test, and microbiological investigations to help confirm the diagnosis.
This study was approved by the hospital research and ethics committee of the ABUTH, Zaria. The purpose and procedures of the study were explicitly explained to all participants, and a duly signed written informed consent was obtained from all participants. They were assured of strict confidentiality and granted the option of opting out of the study at will.
The statistical analysis was performed using the Statistical Package for Social Sciences version 17.0 software (SPSS Inc., Chicago IL, USA). Qualitative variables were analyzed as frequency and percentages. Quantitative variables were expressed as mean ± standard deviation (SD). Odds ratio was used to compare the relative frequencies of rheumatological diseases of HIV-negative vs HIV-positive patients. Multiple logistic regression was used to determine the relative effect size of CD4 count and HIV stage on rheumatological manifestation.
| Results|| |
A total of 400 participants were recruited for the study, comprising of 200 HIV-positive patients and 200 HIV-negative controls. The sociodemographic characteristics of the patients and controls are as shown in [Table 1].
|Table 1 Sociodemographic characteristic of HIV-positive patients and HIV-negative controls|
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Risk factor for HIV transmission
The risk factors for HIV infection in HIV-positive patients was heterosexual in 156 (78.0%) patients, sharing of syringes in eight (4%) patients, blood transfusion in seven (3.5%) patients, intravenous drug abuse (IVDA) in two (1%) patients, one (0.5%) patient stated surgery as a risk factor. Twenty-six (13%) patients were not sure of risk factor of exposure.
Prevalence of rheumatologic disease in HIV-positive patients vs HIV-negative controls
Rheumatologic disease was diagnosed in 56 (28%) HIV-positive patients and in 15 (7.5%) HIV-negative controls as shown in [Table 2]. The odds of occurrence of rheumatologic disease in HIV patients compared to control is 4.8 (CI = 2.61–8.82, P = 0.0001).
|Table 2 Cross-tabulation of the prevalence of rheumatologic disease in HIV-positive patients and HIV-negative controls|
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Pattern of rheumatologic diseases
The distribution of rheumatologic diseases diagnosed in HIV-positive patients and controls is as shown in [Table 3]. Noninfective rheumatologic diseases like polyarthralgia, reactive arthritis, undifferentiated spondyloarthropathy were significantly more common in HIV-positive patients compared to HIV-negative controls. Likewise, infective rheumatologic diseases like septic arthritis, tuberculosis of the spine, and pyomyositis occurred more frequently among HIV-positive patients compared to HIV-negative controls.
|Table 3 Frequency and distribution of rheumatologic disease among HIV-positive patients and HIV-negative controls|
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Prevalence of rheumatological diseases by WHO clinical stage of HIV
The distribution of HIV patients by WHO clinical stage is as shown in [Table 4]. No rheumatologic disease was diagnosed in four patients in HIV stage 1; only one of the 20 patients in HIV stage 2 had rheumatologic disease. Fifteen of the 63 patients in HIV stage 3 and 40 of the 113 patients in stage 4 had rheumatologic disease, respectively. There is an increase in frequency of rheumatological disease with progression in HIV stage, X2 = 6.62, P = 0.036.
|Table 4 Distribution of HIV-positive patients by WHO clinical stage and prevalence of rheumatologic disease|
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CD4 T-lymphocyte count and rheumatologic disease
The mean ± SD CD4 T-lymphocyte count of HIV-positive patients was 326.7 ± 204.6 cells/μL, with a median CD4 T-lymphocyte count of 237.8 cells/μL, and an interquartile range of 168 cells/μL and a range of 2 to 1065 cells/μL. The mean ± SD of HIV-negative controls was 874 ± 141 cells/μL, with a median score of 805 cells/μL, interquartile range of 102 cells/μL is 620 to 1438 cells/μL. The mean CD4 count in HIV-negative controls was significantly higher than in HIV-positive patients (t = 3.29, P = 0.001).
The mean CD4 count of ARV naïve patients was 271.8 ± 158.7 cells/μL, and the mean CD4 count among ARV experienced patients was 381.7 ± 229.9 cells/μL.
The mean CD4 count of patients on ARV was significantly higher than that of ARV naïve patients (t = 3.93, P = 0.000).
The mean CD4 count in HIV patients diagnosed with rheumatologic diseases was 279.1 ± 177.6 cells/μL, whereas the mean CD4 count in HIV positives without rheumatological disease was 345.2 ± 211.8 cells/μL.
The mean CD4 count in HIV-positive patients with rheumatologic disease was significantly lower than that of HIV-positive patient without rheumatologic disease (t = −2.24, P = 0.027).
The mean CD4 count in HIV patients with infective rheumatologic disease tend to be lower than the mean CD4 count of HIV patients with noninfective (inflammatory) rheumatic diseases as depicted in [Table 5].
HIV-positive patients with infective rheumatological disease generally had mean CD4 count below 200 cells/μL, whereas those with inflammatory noninfective rheumatologic disease had CD4 count above 200 cells/μL. The CD4 count grouping of HIV-positive patients is as shown in [Table 6]. The prevalence of rheumatologic diseases was noted to increase with fall in CD4 count. Moreover, there was a statistically significant difference in the prevalence of rheumatologic disease in the different CD4 groups, X2 = 8.8, P = 0.012.
|Table 6 CD4 grouping of HIV patients and prevalence of rheumatologic manifestations in CD4 groups|
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Stepwise backward logistic regression analysis that was done to determine independent predictors of rheumatic disease showed that factors predictive of rheumatological manifestation in HIV patients were HIV stage (P = 0.047) and CD4 T-lymphocyte count (P = 0.049).
| Discussion|| |
Rheumatological diseases are more prevalent among patients infected with HIV, and several studies have alluded to this high prevalence.,,, The occurrence of rheumatologic disease in the setting of HIV increases HIV-related morbidity and occasionally increases mortality., Rheumatologic disorders have been shown to be associated with significant decrease in patients quality of life.,
Although the occurrence of rheumatologic diseases among Nigerians with HIV infection has been highlighted in case reports and series, there is paucity of local studies on the effect of CD4 count and HIV stage on HIV rheumatological manifestations among Nigerians, hence the need for this study.
Demographic characteristic of HIV patients
The demographic characteristics of the HIV-positive patients recruited for this study are similar to the profile of HIV patients seen nationwide, where HIV infection have been noted to commonly affect the younger age group. The modal age group of HIV-positive patients was 25 to 34 years. This is in accordance with the national picture, where HIV is noted to have highest prevalence among the age groups of 30 to 34 years.
There were more females in the study than males, ratio 1.47:1. This is the pattern seen in the ABUTH HIV clinic, where there are more women in attendance at the HIV clinic. This gender disparity may be indicative of higher health seeking behavior of women compared to men.
There appears to be no sex predilection for most HIV rheumatological conditions. Although conditions such as septic arthritis and pyomyositis have been reported to occur more frequently in males.,
HIV was more prevalent among the married persons in this study (50%). Twenty percent of the patients studied were either widows or separated. The latter group is more likely to lack social support to cope with such a challenging condition.
Route of HIV acquisition and rheumatologic disease
With regards to the means of HIV transmission, heterosexual relationship was noted to be the most common implicated route of infection among HIV-positive patients (78%). This is consistent with the figures of >75% by the WHO and the national figure of 80% of HIV transmission, being via heterosexual route. Other routes of HIV transmission in the study included sharing of syringes, blood transfusion (all in rural hospitals), injection drug use, and surgery.
Route of transmission of HIV is important in occurrence of rheumatologic diseases, as previous studies have shown that in HIV patients who were IV drug users or hemophiliacs, there was an absence of reactive arthritis and an increased incidence of septic arthritis.,
Rheumatologic disease among HIV-positive patients and HIV-negative controls
The prevalence of rheumatologic disease was higher in HIV-positive patients (28%) compared to age and gender-matched HIV-negative controls (7.5%). This finding is in consonance with studies done in Nigeria, other African countries,,, and in Argentina and Mexico, that showed significantly higher prevalence of rheumatologic diseases among HIV patients compared to HIV-negative controls, and even alluded to a possible etiological role of HIV in the disproportionate occurrence of these rheumatologic manifestations over and above mere association.,,,
Evidences for a possible etiological role of HIV in rheumatological manifestation can be seen in the ability of HIV to directly invade and cause pathology in the musculoskeletal system,, its causation of depletion of CD4+ T cells with consequent increased risk of musculoskeletal infection, and inversion of CD4:CD8 ratio, resulting in spondyloarthropathic group of diseases,, among other known and evolving etiopathogenic mechanisms.
The difference in the prevalence of rheumatologic disease becomes even more obvious when the proportionality of each rheumatologic disease in HIV-positive and negative patients is taken into cognizance. Polyarthritis and polyarthralgia are five and 10 times, respectively, more likely to occur in HIV-positive patients compared to HIV-negative control. Spondyloarthropathies are 3.5 times more likely to occur in HIV-positive patients compared to HIV-negative controls. The prevalence of musculoskeletal infections like pyomyositis, septic arthritis, and TB spine are each three times higher among HIV-positive patients compared to age and gender-matched HIV-negative controls.
Immunologically driven diseases like rheumatoid arthritis and systemic lupus erythematosus (SLE) were diagnosed only in HIV-negative controls, with no cases occurring in HIV-positive patients. This is not unexpected, given the prominent role that CD4 T-lymphocytes play in the establishment and perpetuation of these conditions.
The depletion of CD4 lymphocytes in HIV patients and increased Th2 cytokines-interleukins-4 and interleukin-10 (IL-4, IL-10) results in the suppression of IL-1 and tumour necrosis factor (TNF) production, thereby conferring some protection against the occurrence of SLE and rheumatoid arthritis (RA) in HIV-positive patients Studies on HIV patients placed on cART have shown that immune reconstitution/restoration following initiation of ART can result in the unmasking of these CD4 T-lymphocytes driven diseases.,,
Pattern of rheumatologic disease among HIV patients
With regards to the distribution of rheumatological disease in HIV-positive patients, inflammatory/infective conditions tend to be predominant. Inflammatory arthritis like HIV-associated polyarthritis occurred in 16.8% of HIV-positive patients, reactive arthritis in 4.5%, and undifferentiated spondyloarthropathy in 4.5% of patients. Infective conditions like pyomyositis (1.5%), septic arthritis (2.5%), and TB spine (1.5%) were also seen. This pattern of rheumatologic disease in HIV-positive patients is similar to those noted in other African countries,,, where studies showed that inflammatory and infective rheumatologic diseases are more prevalent among HIV-positive patients.HIV-specific rheumatologic diseases like diffuse idiopathic lymphocytosis syndrome and painful articular syndrome were also diagnosed in one patient each. These two disease entity have not been previously reported in Nigerian patients.
The bulk of the HIV patients were at advanced stage of disease at the time of diagnosis, with 31.5% of the patients being in stage 3 and 56.5% in clinical stage 4. Presentation at advanced stages of HIV disease is a common feature in Nigerian HIV patients, and several reasons have been proffered for these late presentation.
Regardless of the reasons for late presentation of HIV patients, it does have a bearing on the occurrence and even the pattern of HIV rheumatological diseases, as studies have pointed to the higher prevalence of rheumatologic diseases with progression of HIV., The prevalence of infective rheumatologic disease has also been shown to increase with advanced HIV disease. This was also the finding in this study, where the prevalence of rheumatologic disease was noted to increase with declining CD4 count.
Rheumatological disease-CD4 gradient
There is an association between CD4 count and pattern of rheumatologic disease in this study. Rheumatologic disease-CD4 gradient was noted, as inflammatory rheumatologic disease occurred on average at mean CD4 above 250 cells/μL, whereas infective rheumatologic disease occurred on average at mean CD4 count below 200 cells/μL. This finding might be of potential benefit in the differential diagnosis of rheumatologic disease in HIV patients and also serve to heighten the index of suspicious for HIV infection in individuals with rheumatologic diseases. The predictive value of CD4 count in the diagnosis of rheumatological disease was demonstrated in the study done by Enrique et al.
| Conclusion|| |
Rheumatological diseases are more prevalent in Nigerian patients with HIV infection compared to age and gender-marched HIV-negative controls. CD4 lymphocyte count and HIV stage were significant predictive factors in the prevalence and pattern of HIV rheumatologic manifestations.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]