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In this literature review, we summarize the case reports and other epidemiological data that examine disease severity and outcome of brucellosis in HIV coinfected individuals. A Medline search was conducted to identify case reports and epidemiological analyses on HIV patients with the additional diagnosis of brucellosis infection. In total, we identified 29 cases from 6 main study populations (Belgium, Austria, Spain, Argentina, Kenya, and India) that met these criteria. We reviewed conclusions from each report, identified research gaps, and attempted to discuss the immunology and pathology of brucellosis infection and why it seems brucellosis is not recognized as an opportunistic infection in HIV patients. We conclude that public health workers would benefit from definitive data from larger, randomized controlled trials of brucellosis surveillance in HIV infected persons, particularly in countries where both brucellosis and HIV are prevalent. Although most studies report similar clinical presentation and outcome in HIV-positive and HIV-negative patients, rigorous monitoring is essential to ensure that if there are any adverse effects in HIV infected patients, they are quickly identified and minimized.
Brucellosis, a bacterial infection caused by various species of Brucella (the most pathogenic species being B. melitensis and B. suis), is the most common zoonotic disease in the world with more than 500,000 new cases occurring annually (Pappas et al., 2006). Brucella species are facultative, gram-negative, coccobacilli that are commonly transmitted to humans by either ingesting unpasteurized milk or dairy products from infected animals, or through abrasions of the skin when handling infected animals (Brunette, 2009). Brucella species are also highly infectious in the laboratory via aerosolization, and thus warrants biosafety level-3 precautions.
The geographic distribution of human brucellosis is constantly changing with respect to shifting public health and animal control programs, introduction of cultural or ritual slaughters, as well as socioeconomic status and political discord in endemic countries (Seleem et al., 2009; Pappas et al., 2006). Furthermore, the rapid spread of worldwide globalization and tourism increases the chance that a person may come into contact with an infected animal or ingest unpasteurized milk products thereby infecting themselves.
Developing countries often lack pasteurization laws, animal control or slaughter regulations, as well as complete brucellosis surveillance programs in order to prevent or monitor possible outbreaks. Many of these countries concurrently have widespread HIV epidemics. Other than small studies and individual case reports, there have been no large-scale studies in the literature that look at the immune response to brucellosis in HIV patients, or research that has determined the severity or outcome of brucellosis in HIV-infected persons. Even fewer case reports have been published for AIDS patients with brucellosis, therefore, it is unclear how Brucella affects patients who are further immunologically compromised. Studies of HIV related infections have mainly been concentrated in North America and Europe, where brucellosis is now a relatively rare infection and few cases of brucellosis in HIV-positive patients have been reported. This review of the literature hopes to compile a summary of all studies concerning brucellosis and HIV/AIDS and to elucidate what topics need to be studied further.
INCIDENCE AND IMMUNE RESPONSE
Latest global estimates from 2008 show that 33.4 million people are living with HIV/AIDS with 2.7 million people being newly infected with HIV that year (UNAIDS/WHO, 2008). Patients with HIV are known to be vulnerable to certain intracellular pathogens due to the profound impairment of their B- and T-cell response. The pathogens that predominate in HIV infected persons are commonly referred to as opportunistic infections (OIs) and are an important cause of morbidity and mortality for HIV-infected persons (Brooks et al., 2009). By definition, OIs are caused by organisms of low or no virulence which are non-pathogenic in individuals with an intact immune system or are caused by known pathogens who present in a different than the usual way in immunodeficient individuals or in the form of increased virulence, recurrence, multi-drug resistance or atypical presentation (WHO, 1999). Most OIs occur in HIV infected individuals as the CD4 count declines, with a majority presenting when the CD4 count reaches <200cells/µl (Chitra et al., 2009). Both the clinical course of HIV and the pattern of OIs vary from patient to patient based on socioeconomic standing, level of hygiene, access to care, and also in assorted geographic regions (Gautam et al., 2009). Regions that are high-risk for developing brucellosis include the Mediterranean Basin (Portugal, Spain, Southern France, Italy, Greece, Turkey, North Africa), South and Central America, Eastern Europe, Asia, Africa, and the Middle East. Brucella are present in animals such as goats, sheep, pigs, and cattle, and in wildlife. Brucellosis is an occupational disease among those working with infected livestock, and can infect persons who consume unpasteurized dairy product and/or uncooked meat. Brucellosis is common in countries that do not have a standardized public health system or brucellosis control programs for livestock.
It seems reasonable to suspect that HIV-infected patients may be more vulnerable to brucellosis, however, brucellosis has been described rarely in patients infected with HIV, despite the fact that eradication of intracellular bacteria are largely dependent on cell-mediated immunity (Moreno et al., 1998). In addition, since Brucella infection is largely dependent on the host immune response, it is reasonable to consider that HIV infected patients might be especially prone to developing chronic or recurrent forms of brucellosis in areas with a high prevalence of both infections (Ibarra et al., 2003).
Although acute brucellosis induces both humoral and cell-mediated immune responses, only cell-mediated immunity is necessary for eradication of Brucella (Pedro-Botet et al., 1992). Investigations on the pathogenesis of brucellosis show that the Brucella can survive in phagocytic cells, and cell-mediated immunity plays an important role in immunity against bacteria. Brucella organisms not only resist killing by neutrophils following phagocytosis, but also replicate inside macrophages and nonprofessional phagocytes. Additionally, survival in macrophages, which is considered to be responsible for the establishment of chronic infections, enables bacteria to escape the extracellular mechanisms of host defense such as complement activation and antibody reactions (Dizer et al., 2005).
In a case report published by Pedro-Botet et al., researchers found that although the severe depletion of CD4+ T-cells, one of the primary manifestations of HIV infection, may be a predisposing factor for brucellosis, the increase in the CD4+ T-cell count after recovery from brucellosis in their HIV+ case patient suggests that the Brucella-HIV association may be purely coincidental as the same observation has been described in non-compromised patients as well (Pedro-Botet et al., 1992). Despite the fact that intracellular Brucellae are largely dependent on cell-mediated immunity, HIV+ patients seem to have relatively preserved immunity after Brucella infection (Pedro-Botet et al., 1992). This is comparable with the study Moreno et al. performed in1998, which showed that most cases of brucellosis occur in asymptomatic HIV patients who have relatively preserved immunity. This is in contrast with the well-described association between HIV and tuberculosis- the proportion of patients with brucellosis who are coinfected with HIV seems to be low and not significantly different to that in HIV-negative persons (Pape et al., 1993). While brucellosis does not seem to be immunologically associated with HIV infection, the significance of this implication is still not understood.
PUBLISHED CASE REPORTS AND STUDIES
Review of the medical literature showed that very few cases of brucellosis in HIV-infected patients have been reported. In a serological study performed by Paul et al. in Nairobi, Kenya, researchers looked at sera from 100 individuals (65 of whom were HIV-positive) and tested them for Brucella-specific antibody. (Brucella serology was done retrospectively on stored sera from patients from a previous study). Twenty-five percent of HIV-positive and 14% of HIV-negative patients had anti-Brucella IgG and 12% of HIV-positive and 17% of HIV-negative patient had anti-Brucella IgM, which shows relatively high levels of exposure in the study population. Only two HIV positive patients tested positive with antibody responses to Brucella comparable to those of immunocompetent individuals and were later confirmed to be infected with B. melitensis. Patient 1 and 2 did not show clinical features of severe immunodeficiency; the CD4+ count for patient 1 was 890x106/L, while the CD4+ count for patient 2 was not identified in the case report. Due to the small sample size, however, the authors concluded that there was no significant association between Brucella serology and HIV status (Paul et al., 1995). They also concluded that HIV infection does not seem to affect the accuracy of anti-Brucella antibody detection (by ELISA), the clinical course of brucellosis, or the successful treatment of brucellosis.
In another study performed in India by Sarguna et al. (2002), a brucellosis case report was published for a 21-year old, HIV-positive male (CD4+ count was not provided, however, total lymphocyte count was 7600/mm3). A diagnosis of brucellosis was made after high agglutinin titers (640) were confirmed by the standard agglutination test (SAT). The patient responded well to a 6-week antibiotic treatment regimen of tetracycline and streptomycin. The authors noted that the presentation of this case was typical and that the patient had relatively preserved immunity. The authors of this paper similarly concluded that the epidemiology, clinical presentation, diagnosis, response to therapy and outcome are analogous to those observed in non-HIV infected patients.
Similarly, the first case report of a Brucella canis infection in an HIV-positive patient was reported in 2009 (Lucero et al., 2009). This patient presented with a febrile syndrome and had a CD4+ count of 385 cells/µl. The patient received antibiotic treatment (doxycycline/ciprofloxacin) and showed improvement as soon as one week after initiating therapy. No symptoms of relapse were detected during the follow-up visit (22 months post diagnosis). The clinical course of this case was similar to those shown in immunocompetent patients and HIV status was not deemed to play an incendiary role in infection, treatment or case management.
In 1992, Pedro-Botet et al., described two case patients and suggested that Brucella infection was coincidental in HIV-positive patients. One case patient with a CD4+ count of 150x106/L, improved after 21 days of treatment with doxycycline and rifampin, however, the patient was lost to follow-up after being discharged from the hospital. The second HIV-positive patient (CD4+ count of 172x106/L) was prescribed doxycycline and rifampin and was said to have recovered fully in 30 days. The patient was monitored 6 months post-treatment and remained asymptomatic, with no relapse of brucellosis, and no additional HIV-related complications. His CD4+ count 6 months post-treatment was also significantly higher at 420x106/L. The authors concluded that the increase in T-cell count after recovery may suggest that the Brucella-HIV association may be causal.
In a short case report researching FDG-PET for use as a tool to monitor chronic osteomyelitic brucellosis (a rare complication of Brucella infection), Zaknun et al. published images before treatment as well as 6 weeks following a multiple antibiotic regimen (regimen was not specified). The case patient was a 33-year old HIV patient with a CD4 count of 216 cells/µl. The image before showed significant disease burden, while the image taken after treatment showed a significant reduction in disease burden. However, the authors were unable to address whether or not this complication occurred due to HIV coinfection.
In another more complicated case study in Belgium, a 35-year old male with AIDS was admitted to the hospital after an epileptic fit (Galle et al., 1997). Six months earlier, he had undergone a brain biopsy which showed infection with toxoplasmosis. After treatment of both toxoplasmosis and HIV infection, his CD4 count remained <200 cells/µl. One month before the current seizure, the patient recalled travelling to Portugal where he consumed fresh goat cheese; he also remembered exhibiting an influenza-like illness during his stay. Upon admission to the hospital, physicians resected the bone flap and took cultures from an extradural abscess that had formed which yielded both Staphylococcus epidermidis and Brucella melitensis. The authors were unsure whether or not the postoperative lesion allowed for a secondary colonization center for the bacteria, or if the development of the abscess was solely due to B. melitensis or S. epidermidis. However, three months after antibiotic treatment (), the patient was asymptomatic with no complications and had not had a relapse of brucellosis.
The largest epidemiological study (to date) that examined the relationship between HIV and brucellosis was reported by Moreno et al. They included Spanish hospitals in areas where brucellosis was endemic, yet, at the end of their study, they reported a low rate of brucellosis in HIV-infected patients (Moreno et al., 1998). Out of the twenty-three hospitals sampled from 1981 to 1995, only 12 HIV-infected patients in seven hospitals were diagnosed with brucellosis. The authors concluded that HIV infection does not seem to increase the incidence of brucellosis and that the clinical outcome is similar to those observed in non-HIV infected patients (Moreno et al., 1998).
In a single case report published in 2000, Fernandez et al. reported that clinical characteristics, diagnosis, response to therapy and outcome of brucellosis in an HIV-positive patient appeared to be similar to that observed in HIV-negative patients. However, this case patient did display a relapse rate that was higher than is normally found in immunocompetent hosts. This higher relapse rate was mirrored in 2003 by Ibarra et al. in a single case of relapsing brucellosis in an HIV-positive patient.
In 1992, Martín et al. report a case of brucellosis in a 34 year old who had been diagnosed with HIV 6 years prior. Upon diagnosis with brucellosis, CD4 was 570mm3. After a 45 day regimen of rifampicin and doxycycline, the patient was clinically well and asymptomatic. At 6 months post treatment, the patient suffered a febrile relapse and is treated with a second course of combination therapy consisting of streptomycin, doxycycline and zidomidina.
While the clinical progress was favorable, seven months of the patient being asymptomatic, a routine blood culture revealed continued infection with Brucella. At this time, CD4 count was 228mm3. Physicians noted that the patient was currently in the middle of a third cycle of treatment with doxycycline and rifampicin at the time of publication. Also, the patient was reported to have adequately followed treatment regimens and had left the environment in which he was originally infected (therefore, they believe possibility of re-infection is low). They concluded that co-infection with HIV allowed for easier relapse of brucellosis, which raises problems that are seen in other opportunistic infections in HIV patients. The authors cite that co-infection with HIV may lead to difficulty reaching therapeutic treatment level (Martin, 1992). As an intracellular bacterium, it may be more difficult to treat in HIV patients which may result in more frequent recurrences. This raises other questions and shows the importance of the patient's immune response to infection with Brucella
Recently, Abdollahi et al. (2010), performed a cross-sectional survey of brucellosis serology in HIV infected patients and healthy controls. They found that positive brucellosis serology was significantly higher in HIV-infected patients than in controls (73.3% vs. 30%, respectively, odds ratio 6.42, p<0.001). It was also higher in males than females, p=0.001. Brucellosis-infected patients had significantly lower hemoglobin and white blood cell counts compared with brucellosis-uninfected patients (p<0.001). In HIV-positive patients, white blood cell count was significantly lower in brucellosis-infected than brucellosis-uninfected patients (p<0.05). They concluded that brucellosis infection is an important infection in HIV-infected patients. The treatment of brucellosis may be of great clinical importance in the management of HIV infection in a brucellosis endemic country like Iran.
Lawaczeck et al. 2010:
There has been an interesting correlation between brucellosis rates in HIV-infected persons.
There has been varying associations between brucellosis rates in HIV-infected persons. Larger studies would be helpful in determining the immunologic role of chronic brucellosis in both HIV- and non-HIV infected patients. Studies that examined the role of relapse vs. possible re-infection would be of interest, as well as possible outcome differences in HIV vs. AIDS patients. Lastly, the appearance of additional OIs would be of interest while studying the immunologic relationship within a subset of patients.
In areas of the world where HIV rates are high (sub-Saharan Africa, Middle East, Asia, etc.), there is also often a lack of pasteurization awareness and therefore a high rate of brucellosis as well. Larger studies that examined the aforementioned relationships between immune competence and brucellosis would raise the statistical significance of outcomes versus individual case reports that are often published. If brucellosis is different from other bacterial infections, it would be of interest to study what makes Brucella react differently to the host immune system of an HIV-infected individual. Other diseases like melioidosis are rarely reported within HIV-infected patients, however outcome may be disturbed.
Many of these countries concurrently have widespread HIV epidemics. Other than small studies and individual case reports, there have been no large-scale studies in the literature that look at the immune response to brucellosis in HIV patients, or research that has determined the severity or outcome of brucellosis in HIV-infected persons.
While current research shows that the epidemiology, clinical presentation, diagnosis, response to therapy, and outcome are similar to those observed in non-HIV infected patients (Moreno et al, 1996),
In a letter to the editor in a 1983 issue of Irish Medical Journal, a physician makes a comparison between chronic brucellosis and AIDS, stating that the acquired immune suppression associated with chronic brucellosis appears to be similar to AIDS and that coumarin may be useful in treatment of both conditions (Thornes, 1983). Further research on this observation…
Investigations on the pathogenesis of brucellosis show that the Brucella can survive in phagocytic cells, and cell-mediated immunity plays an important role in immunity against bacteria. They studied whether supplementation of levamisole with conventional antibiotic therapy would improve anergy against Brucella and concluded that it had no immunostimulating effect on the basis of lymphocyte subgroups ratios measured and the ability of phagocytosis. More larger clinical and laboratory trials aare necessary to investigate the immunological and physiological effects of levamisole on TH1 subtyppes and cytokine secretion.
Investigations on the pathogenesis of brucellosis show that the Brucella can survive in phagocytic cells, and cell-mediated immunity plays an important role in immunity against bacteria. Brucella organisms not only resist killing by neutrophils following phagocytosis, but also replicate inside macrophages and nonprofessional phagocytes. Additionally, survival in macrophages, which is considered to be responsible for the establishment of chronic infections, enables bacteria to escape the extracellular mechanisms of host defense such as complement activation and antibody reactions.
Brucella can modulate host immune response, leading to T-cell anergy and chronic infection.
Few cases of brucellosis have been reported from individuals infected with HIV, and the relationship between brucellosis and HIV infection remains largely uninvestigated, probably because most studies on HIV have been conducted in areas of the world where brucellosis is now rarely diagnosed or where surveillance is lacking.
While it seems reasonable to suspect that HIV-infected patients are vulnerable to other intracellular pathogens, a review of the literature seems to indicate that HIV infection does not seem to significantly influence the presentation or outcome of disease due to brucellosis. Despite the fact that OIs tend to cause substantial morbidity, necessitate toxic therapies, and shorten the survival of people with HIV infection, HIV coinfection does not seem to increase the incidence of brucellosis and does not appear to be a major risk factor for brucellosis (Gauyam et al., 2009). However, more research is needed to further describe: 1) the epidemiology of concurrent HIV/Brucella infection, 2) the clinical characteristics during concurrent infection, 3) diagnostic response to therapy in immunocompromised patients, and 4) further elucidate the outcome of brucellosis in patients infected with HIV (Moreno et al., 1996).
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