Infections in patients with aplastic Anemia in Chiang Mai University

Aplastic anemia (AA) is characterized by an empty or hypocellular bone marrow that leads to hematopoietic failure and pancytopenia [1, 2]. The immune-mediated destruction of hematopoietic stem cells by T-lymphocytes is implicated in the pathogenesis [1]. In addition, AA may relate to environmental exposures including chemicals, medical, and infectious agents as well as individual host factors [1‐3]. The disease occurs more frequently in Asia than in the West, with higher incidence rates for 2- to 3-fold [3]. In Thailand, the incidence of AA appears to vary geographically. There were 3.9 cases per million persons in Bangkok, 3.0 per million in Songkla, and 5.0 per million in Khonkaen [4].

Infections are major causes of morbidity and mortality in this population as a consequence of neutropenia [1, 2, 5, 6]. The study from M.D.Anderson Cancer Center showed 41% of AA patients died from infection [5]. In that study, bacterial infection, mainly gram-positive cocci was the most common organism (55%) [4, 5]. However, fungal infections were significant causes of death [5, 6]. Over the past two decades, the development of effective treatments of AA including immunosuppressive therapy with antithymocyte globulin plus cyclosporine (ATG-CsA) and allogeneic hematopoietic stem cell transplantation (HSCT) [1, 2] as well as advanced in anti-infective therapies led to striking decreased in infection-related mortality [7].

Since there was no previous study about characteristics of infections in patients with AA in Chiang Mai University. Therefore, we evaluated the prevalence of infection, associated pathogens, and outcomes of infectious episodes (IEs) in patients with AA who were treated at Chiang Mai University.

Infection is major complication and lead to morbidity and mortality in AA patients [1, 2, 5, 6]. The current study that included severe AA of approximately two-third of the patients showed the prevalence of infection was 32.8%. The previous study in years 1994–2000 from M.D.Anderson Cancer Center revealed the high prevalence of IEs of 81% (42 from 52 patients with 104 IEs) although proportion of severe AA was about half of patients [5]. In the studies that included only AA patients who received immunosuppressive therapy, the prevalence of infections were 68.6% in study during 1978–1989 [6] and 75–86.6% in the trial during 2005–2010 [12]. The relatively low prevalence of infection in the current study might be explained by difference in time of studies, proportion of patients with severe AA, patients’ comorbidities, as well as treatment modalities and infectious prophylaxis. It should be noted that only about one-third of patients in the current study received ATG-CsA while the majority of them were treated with anabolic hormone.

Treatment with immunosuppressive therapy with ATG-CsA is effective in patients with severe AA with response rate of 50–70% [13, 14]. However ATG-CsA suppresses T-cell function and may increase risk of infections [15]. In the current study, eleven IEs occurred in 23 patients who were receiving ATG-CsA. As a result, the prevalence of infections in this subgroup of patients was 47.8% that was still lower than prior mentioned studies [6, 12]. These findings might be partially explained by selection bias to give this treatment to young and fit patients in Thailand due to economic concern. The treatment with ATG-CsA was associated with a trend toward greater risk for infection but it is not clearly demonstrated in this study (RR 2.152, 95%CI 0.892–5.193, p = 0.081). This might be due to immunosuppressive effect from ATG-CsA or severe neutropenia since all patients who received this treatment must have severe AA. The authors excluded IEs that occurred in AA patients who underwent HSCT because IEs that occur in this group were also influenced by HSCT-related complications [15].

The current study confirmed that the important risk factor of infection in patients with severe AA is severe neutropenia [5‐7]. Approximate 80% of IEs in this study occurred in patients with ANC < 500/mm³. Moreover, severe neutropenia was also associated with severe IEs, shorter duration from diagnosis to IEs, and higher mortality rate with mean ANC of the patients who died during this study was 149/mm³. Other risk factors that were reported to associate with infections included low absolute monocyte count and the presence of an indwelling central venous catheter [6].

According to pathogen that caused infections in AA patients, the pattern of bacterial infections in United States was changed over the last three decades [7]. First of all, there was increased prevalence of gram-positive bacteria. For instance, gram positive bacteria, especially gram-positive cocci, accounted for 76% of all bacterial infections in study from M.D.Anderson Cancer Center from 1994 to 2000 [5]. Secondly, there was decreased prevalence of infections due to coagulase-negative Staphylococcus species (from 53 to 25%) whereas increased prevalence of infections due to gram-positive bacilli (from 2.3 to 15%), and no significant change in the prevalence of infections due to gram-negative bacilli (from 46 to 41%) [7]. This finding was comparable with the current study since the prevalence of gram-positive bacteria (47.1%) was slightly less than gram-negative bacteria (52.9%) and gram-positive bacilli especially Bacillus spp. was the most common gram-positive bacteria. The low proportion of patients had central line in this study might influence the relatively low incidence of gram-positive bacterial infections. It is noteworthy that nosocomial pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa were the most common gram-negative bacterium identified. Acinetobacter baumannii is an emerging organism in patients with health care associated infections that has significant morbidity and mortality rates [16]. Bacterial infection caused by Acinetobacter baumannii was observed in one-third of patients who died in this study. Consideration of antibacterial prophylaxis against gram-negative bacilli especially fluoroquinolone was recommended in patients who expected to experience profound neutropenia for more than 7 days after chemotherapy [17]. However use antibacterial prophylaxis in AA should be based on the local policy according to the British Society for Standards in Haematology guideline [18]. According to the organisms found in this study, fluoroquinolone is probably not the effective antibiotic prophylaxis for AA patients.

Invasive fungal infections were also common pathogens in patients with AA with Aspergillus spp. and Candida spp. were the most frequently fungal infection found [5‐7]. The prevalence of fungal infection in the previous studies were around 18–23% and the proportion of Aspergillus spp. to Candida spp. infections were varied from 0.85–1.57 [5, 6]. The current study showed that 21.7% of microbiological documented IEs caused by fungal infection with Aspergillus spp. but no Candida spp. was identified. It might be due to variation of degree and duration of neutropenia, immunosuppressive treatment together with types and proportion of patients who receive antifungal prophylaxis.

The significant cause of mortality of AA patients was described to be from infections. In the current study, patients with infections had significantly shorter survival than patients without infection. All patients (100%) who died in this study were resulted from infection. This proportion was higher than previous studies that reported around 40–60% [5, 6]. Overall, the infection-related mortality in AA patients in the current study was 9% that was closed to data from United States (11%) [7]. The finding that the majority of patients died from bacterial infection whereas only 16.7% died from fungal infection was correlate with decreased prevalence of invasive fungal infections in AA patients [7].

The main limitation of this study was the retrospective design that might result in incomplete data gathering including a media follow-up of all patients. The prevalence of some infections especially viral infection that required advanced laboratory testing was also lacking. The enrolled patients in this study had variation in severity as well as treatment that might lead to difficulty in data interpretation. Finally, the effect of some variables such as very severe AA (ANC < 200/mm³) and antimicrobial prophylaxis to IEs were not analyzed.