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Associated factors and prognostic implications of neutropenia in individuals with HIV/AIDS

Virology Journal volume 22, Article number: 6 (2025) Cite this article

Abstract

Background

Neutropenia frequently presents as a hematological manifestation among people living with HIV/AIDS (PLWHA). This study explores the factors associated with neutropenia in PLWHA and its prognostic significance.

Methods

We conducted a retrospective case-control study of the clinical data from 780 cases of individuals living with HIV/AIDS, who were admitted to Zhongnan Hospital of Wuhan University over the period from January 2016 to September 2020. We categorized the patients into two different groups based on absolute neutrophil Count (ANC): neutropenia group (ANC < 2.0 × 109/L, 33.7%) and non-neutropenia group (ANC ≥ 2.0 × 109/L, 66.3%). We analyzed the co-infections, blood routine test, infection indicators, lymphocyte subpopulation, bone marrow cell cytology, bone marrow morphology in both groups. Additionally, we analyzed the prognosis of the patients.

Results

The results of multifactorial logistic regression showed that increased C-reactive protein (CRP) (p<0.001, adjusted odds ratio [AOR] = 0.984, 95% CI:0.975–0.993), Monocyte (MONO) (p = 0.011, AOR = 0.091, 95% CI: 0.013–0.637), CD19+B lymphocytes (p = 0.008, AOR = 0.990, 95% CI: 0.983–0.997), Bone marrow granulocyte (p = 0.017, AOR = 0.936, 95% CI: 0.883–0.992) were protective factors for neutropenia in PLWHA. Kaplan–Meier survival curve analysis showed that Grade 2 neutropenia group (ANC<0.5 × 109/L) had a worse prognosis than Grade 1 neutropenia group (0.5 × 109/L ≤ ANC<2 × 109/L, p = 0.019) and non-neutropenia group (ANC ≥ 2.0 × 109/L, p = 0.008). Older age (p = 0.002), lower hemoglobin levels (p = 0.001), and a reduced proportion of bone marrow granulocytes (p = 0.002) were associated with a poorer prognosis in PLWHA.

Conclusion

HIV infection can lead to reduced neutrophil counts and damage to the immune system through multiple pathways. Severe neutropenia results in a worse prognosis, making timely diagnosis and treatment of neutropenia in this population essential.

Introduction

Neutrophils, constituting 50–70% of the total leukocyte population in human peripheral blood, serve as the primary responders of the innate immune system [1]. These cells are equipped with an extensive arsenal of defense strategies, including the phagocytosis and destruction of foreign entities, the release of protein hydrolases, the generation of reactive oxygen species, and the formation of neutrophil extracellular traps (NETs) [2]. Neutropenia was frequently observed in PLWHA. In 1983, three of seven PLWHA in New York State correctional facilities were reported to have leukopenia [3]. In 1999, a decade-long study conducted from 1982 to 1993 in Brussels, Belgium, revealed that 484 out of 1870 patients with HIV experienced neutropenia [4]. A recent study reported that 1034 of 9426 (11%) PLWHA had developed Grade 1 neutropenia (ANC < 1,300 cells/mm3) and 448 of 9426 (4.8%) had developed Grade 2 neutropenia (ANC < 500 cells/mm3) [5]. A decrease in the number of neutrophils led to a decrease in defense against microbial invaders, thus leading to an increased incidence of bacterial infections among PLWHA [6,7,8], as well as contributing to increased mortality in HIV-infected patients [9, 10]. However, some studies held a different opinion. As early as in 1991, Farber BF found that patients with HIV infection and modest neutropenia (ANC < 1000 cells /mm3) had no increased risk of bacterial infection [11]. A prospective cohort study conducted in 2013, which included 418 patients with co-infections of HIV and hepatitis C virus (HCV), concluded that neutropenia was not an independent risk factor for severe infections [12]. The reason for this discrepancy is unclear. In this study, our analysis revealed that individuals in the neutropenia cohort demonstrated an increased propensity for hepatitis C virus infection (p = 0.001), oral candida (OC) (p < 0.001), talaromyces marneffei (TM) (p < 0.001), pneumocystis pneumonia (PCP) (p < 0.001) compared with that of the non-neutropenia group. Grade 2 neutropenia group had a worse prognosis than Grade 1 neutropenia group and non-neutropenia group while the latter two groups showed no difference.

The etiology of neutropenia in patients with HIV is multifaceted, including detrimental effects of viruses on hematopoietic cells, administration of myelotoxic therapeutic drugs, complications arising from secondary infections and malignancies, and the influence of confounding factors that impair myelopoiesis. Despite these complexities, large-scale real-world studies examining bone marrow cytology and morphology have been lacking. So we investigated the pathogenesis of neutropenia in PLWHA in terms of bone marrow cytology and bone marrow morphology.

Design and methods

This study included 780 HIV-infected patients (PLWHA), all of whom satisfied the diagnostic criteria specified in the “AIDS Diagnosis and Treatment Guidelines (2018 Edition)” published by the Chinese Medical Association. These individuals received treatment at Zhongnan Hospital from January 2016 to October 2020. This study complies with “the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)” guidelines. NCT05808803.

Inclusion criteria for participation in this trial were as follows: availability of routine blood information, undergoing bone marrow aspiration, and aged 18 years or older. Exclusion criteria included individuals younger than 18 years, as well as those without available routine blood information and prognostic information, and individuals who did not receive bone marrow aspiration. Ultimately, 780 patients were included in this study. Based on neutrophil count, the patients were divided into two groups: the neutropenia group (ANC < 2.0 × 109/L, 33.7%) and the non-neutropenia group (ANC ≥ 2.0 × 109/L, 66.3%). We collect the demographic and clinical data of PLWHA, including co-infections, peripheral blood cells, infection indicators, lymphocyte subpopulations, bone marrow cytology and bone marrow morphology.  1.

We used the independent samples’ t-test to compare the means of continuous variables with normal distributions. Nonparametric tests were utilized to evaluate differences in variables that did not follow normal distribution. To compare categorical variables, the χ2 test was applied. To analyze the factors contributing to neutropenia, we employed both univariate and multivariate binary logistic regression models. Kaplan–Meier survival curve analysis was employed to evaluate the effect of neutropenia on the prognosis of people living with HIV/AIDS. Data analysis was carried out using IBM SPSS, version 25.0 (IBM SPSS Inc., Armonk, NY, USA), p < 0.05 indicates a statistically significant difference.

Results

Clinical characteristics and co-infections of PLWHA

This retrospective case-control study included 780 PLWHA, of whom 646 (82.8%) were male. The participants had a median age of 43 years (interquartile range [IQR] 32, 52). In the neutropenia group, 204 patients (77.6%) were male with median age 44 years, while in the non-neutropenia group, 442 patients (85.5%) were male and the median age was 42 years. A notable difference in gender distribution was observed between the two groups (p = 0.006). The proportion of individuals aged 45 and older in the neutropenia group was higher than that in the non-neutropenia group. (p = 0.048). Patients in the neutropenia group demonstrated a higher likelihood of HCV (p = 0.001), OC (p < 0.001), TM (p < 0.001), PCP (p < 0.001). C-reactive protein levels were lower in patients in the neutropenia group (p = 0.01). The clinical characteristics and co-infections in PLWHA was shown in Fig. 1 and Table 1.

Table 1 Clinical characteristics and co-infections of PLWHA
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Fig. 1
figure 1

Clinical characteristics and co-infections of PLWHA. ***p < 0.001

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Peripheral blood cells and lymphocyte subpopulation of PLWHA

Our findings indicated that the counts of leukocytes, erythrocytes, hemoglobin, platelets, lymphocytes, monocytes, eosinophils, and basophils were significantly reduced in the neutropenia group (p < 0.01). CD16+CD56+ lymphocytes were lower in the neutropenia group (p = 0.006), and CD19+ lymphocytes were similarly lower in the neutropenia group (p = 0.001) (Table 2; Fig. 2).

Table 2 Infection indicators, peripheral blood cell counts, and lymphocyte subpopulation between the two groups
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Fig. 2
figure 2

Comparison of Infection indicators, peripheral blood cells, and lymphocyte subpopulation between the two groups. *p < 0.05, **p < 0.01, ***p < 0.001

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Comparison of bone marrow cytology and bone marrow morphology of PLWHA

We analyzed the bone marrow cytology and bone marrow morphology in the two groups (Table 3). Regarding bone marrow cytology, no significant differences were observed in the levels of bone marrow hyperplasia between the two groups. The proportion of bone marrow granulocytes was significantly lower of the neutropenia group compared to the non-neutropenia group (P < 0.001), Whereas the percentage of bone marrow erythrocytes showed the opposite results (P < 0.001). The granulocyte-to-erythrocyte ratio was significantly greater in the non-neutropenia group (p < 0.001). The percentage of bone marrow lymphocytes showed the same results (P = 0.001). Furthermore, there were no statistically significant differences observed in the total counts of bone marrow monocytes and megakaryocytes, nor in the percentage of thrombocytogenic megakaryocytes between the two groups (Fig. 3). Next, we analyzed marrow morphology between the two groups. Increases in granularity and thickening were observed to be more prevalent in the non-neutropenia group. (p = 0.019). Likewise, outside-in plasm was more prevalent in the non-neutropenia group (p = 0.039). On the other hand, granulocytic shift to left was significantly more common in the neutropenia group (p = 0.024). Basophilic stippling was observed to be more prevalent in the neutropenia group (p <0.001).

Figure 4 illustrates the occurrence of neutropenia among individuals with a variety of bone marrow morphologies. Figure 5 shows the distinctive morphological alterations in PLWHA, including Increased granularity and thickening, Outside-in plasm, Granulocytic shift to left, and Basophilic stippling.

Table 3 Comparison of bone marrow cytology and bone marrow morphology between the two groups
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Fig. 3
figure 3

Comparison of bone marrow morphology between the two groups. (A) Granulocytes, (B) Erythrocytes, (C) Lymphocytes. ***p < 0.001

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Fig. 4
figure 4

Prevalence of neutropenia in patients with different bone marrow morphology. *p < 0.05, ***p < 0.001

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Fig. 5
figure 5

Typical morphological changes in bone marrow cells in people living with HIV/AIDS. (A) Increased granularity and thickening. (B) Outside-in plasm. (C) Granulocytic shift to left. (D) Basophilic stippling

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Associated factors of neutropenia in PLWHA: univariate and multivariate logistic regression analysis

Univariate analysis indicated that Female (p = 0.006), Age ≥ 40 years (p = 0.048), Hepatitis C (p = 0.001), Bone marrow erythrocytes (p<0.001), Bone marrow lymphocytes (p<0.001), Outside-in plasm (p = 0.040), Granulocytic shift to left (p = 0.024), Basophilic stippling (p<0.001) positively correlated with neutropenia, while CRP (p = 0.024), WBC (p<0.001), RBC (p<0.001), HGB (p<0.001), PLT (p<0.001), LYM (p = 0.005), MONO (p<0.001), EO (p = 0.030), BASO (p<0.001), CD16+CD56+ lymphocytes (p = 0.038), CD19+ lymphocytes (p = 0.005), Bone marrow granulocytes (p<0.001), Increased granularity and thickening (p = 0.019) negatively correlated with neutropenia in PLWHA. Owing to the issue of collinearity, WBC and RBC were excluded from the model. Multivariate analysis further determined that CRP (p<0.001, AOR = 0.984, 95% CI:0.975–0.993), MONO (p = 0.011, AOR = 0.091, 95% CI: 0.013–0.637), CD19+ lymphocytes (p = 0.008, AOR = 0.990, 95% CI: 0.983–0.997), Bone marrow granulocytes (p = 0.017, AOR = 0.936, 95% CI: 0.883–0.992) were independent protective factors (Table 4).

Table 4 Factors associated with neutropenia in PLWHA by univariate and multivariate analysis
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Effects of Neutropenia on the prognosis of PLWHA

We conducted both univariate and multivariate Cox regression analyses to evaluate the survival outcomes of PLWHA. The results demonstrated that an older age, lower hemoglobin levels, and a reduced proportion of bone marrow granulocytes were associated with a poorer prognosis in PLWHA (Table 5).

Table 5 Univariate and multivariate COX analyses for OS in PLWHA
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We employed the Kaplan–Meier method, along with a two-sided log-rank test, to assess the factors influencing survival in people living with HIV/AIDS (PLWHA). Data collection was conducted on April 4, 2022. The median follow-up duration was 50 months, with a range of 1 to100 months. The analysis of the Kaplan–Meier survival curves revealed that Grade 2 neutropenia group (ANC<0.5 × 109/L) had a worse prognosis than Grade 1 neutropenia group (0.5 × 109/L ≤ ANC<2 × 109/L, p = 0.019) and non-neutropenia group (ANC ≥ 2.0 × 109/L, p = 0.008). The prognosis of the Grade 1 neutropenia group (0.5 × 109/L ≤ ANC<2 × 109/L) was not significantly different from that of the non-neutropenia group. (p = 0.632). (Fig. 6).

Fig. 6
figure 6

Comparison of 100-month survival of patients in the non-neutropenia group, Grade 1 neutropenia group, and Grade 2 neutropenia group by Kaplan–Meier survival curves

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Discussion

Neutropenia and myelosuppression are commonly observed in PLWHA. In this study, we identified 263 patients with neutropenia, which constituted 33.7% of the overall cohort examined. We identified decreased bone marrow granulocyte ratio, decreased peripheral blood mononuclear cell count, decreased B-lymphocyte count and decreased CRP as risk factors associated with the development of neutropenia. Additionally, an ANC count of ≤ 0.5 × 10^9/L was linked to a poorer prognosis in individuals living with HIV/AIDS (PLWHA).

We concluded that decreased bone marrow granulocyte ratio represented as independent risk factor for neutropenia in PLWHA. Because of the relative short lifespan of neutrophils in the systemic circulation, maintaining normal levels of neutrophils in the peripheral blood is largely dependent on the hematopoietic tissues producing sufficient numbers of neutrophils on a daily basis. Previous studies have shown that HIV infection can impair the function of hematopoietic stem/progenitor cells (HSPCs) [13, 14]. In vitro investigations have revealed that HIV is cytotoxic to infected HSPCs, resulting in the death of these hematopoietic precursors [15]. Apart from this, HIV is also capable of infecting a variety of cell types in the bone marrow hematopoietic niche, leading to an increase in macrophage-like cells and a decrease in the number of fibroblastic population [16]. HIV infection of various bone marrow stromal niche cell types may mediate myelosuppression and impair granulopoiesis by disrupting cellular interactions between niche cells and hematopoietic cells. This disruption weakens the supportive role of niche structures for hematopoietic cells and alters the production of cytokines and hematopoietic growth factors by niche cells, thereby compromising the humoral regulation of myeloid/granulocytic lineage development within the bone marrow [16,17,18].

Decreased peripheral blood mononuclear cell count was a risk factor for neutropenia. Neutrophils and monocytes are derived from a common progenitor, granulocyte-macrophage (GM) progenitors, which implies a possible quantitative correlation between monocytes and neutrophils [19]. Monocytes and macrophages serve as essential components of the innate immune system. And they also play pivotal roles in the initiation of adaptive immunity. Monocytes enter the peripheral circulation after developmental differentiation in the bone marrow from stem cells of the granulo-monocytic lineage. Studies have shown that both monocytes and macrophages can be infected by HIV-1 and may serve as viral reservoirs [20,21,22]. Following HIV infection, there is a progressive decline in the production of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) by blood monocytes. Notably, this reduction in GM-CSF production exhibits a significant correlation with the viral load present in the peripheral blood mononuclear cells of the patient [23, 24]. HIV may have a substantial impact on the onset of neutropenia by direct invasion of stem cells of the granulo-monocytic lineage or by influencing the reduction of GM-CSF production.

In addition, decreased CD19+B-Lymphocytes was also a risk factor for neutropenia. B-Lymphocytes, responsible for the secretion of antibodies, have a substantial impact on mediating the humoral immune response to viral and bacterial infections by neutralizing, conditioning, mediating cell death through antibodies, and activating complement pathways. Additionally, CD19+B-lymphocytes play a crucial role in regulating the immune system through antigen presentation and cytokine secretion. Researches have demonstrated that prolonged HIV-1 infection leads to a reduction in peripheral blood B-cell count and modifications in subpopulation proportions. Furthermore, it causes impairments in B-cell function, resulting in reduced antigen-specific antibody-secreting and cytokine-secreting capabilities as well as a decline in its specific immune response function [25, 26].

C-reactive protein is a non-specific biomarker of acute phase inflammation, which is elicited by interleukin (IL)-1 and IL-6. Studies have shown that C-reactive protein concentrations increase with infection and are independent of HIV status [27, 28]. What is clear is that neutropenia leads to a greatly increased risk of opportunistic infections. Interestingly, lower concentrations of CRP were associated with neutropenia in our findings. In PLWHA, infection with tuberculosis led to high levels of CRP, whereas the increase in CRP concentration in patients infected with Talaromyces marneffei and Pneumocystis pneumonia was significantly lower than that in patients infected with common bacterial pathogens [27, 29,30,31]. In this study, patients in the neutropenia group were more likely to be infected with TM (p < 0.001), PCP (p < 0.001) compared with the non-neutropenia group while there was no significant difference in the proportion of TB infections between the two groups. This may be one of the reasons why CRP was lower in the neutropenia group, and another reason may be that monocytes are lower in the neutropenia group, and IL-1 and IL-6 secreted by monocytes and macrophages promotes CRP synthesis [32, 33].

In summary, we believe that there are at least three causes for neutropenia during HIV infection. First, the cytotoxic effect of HIV on HSPCs results in a reduction in neutrophil production. Second, HIV disrupts the hematopoietic growth factor and cytokine environment within the niche network, leading to a significant reduction in the production of G-CSF by bone marrow stromal cells. HIV leads to a decrease in monocytes in the peripheral blood, resulting in a decline in the secretion level of GM-CSF, which in turn causes a reduction in granulocytes. Finally, it is interesting to note that there was no statistically significant difference in CD4+ lymphocytes between the two groups of patients, but CD19+ lymphocytes were significantly lower in the neutropenia group. This suggests that the humoral immune response in HIV patients is more closely associated with neutropenia, though the specific pathogenesis require further investigation.

In this study, we found that ANC<0.5 × 109/L in PLWHA leads to worse prognosis. Severe neutropenia, coupled with the deterioration of adaptive immunity, significantly elevates the risk of life-threatening secondary infections. Neutropenia serves as a dose-limiting factor for various antimicrobial agents, potentially complicating the management of primary HIV infection and its associated secondary infections [4, 34, 35].Therefore, providing treatment for HIV-positive patients is critical. HIV-positive patients undergoing combination antiretroviral therapy that excludes Zidovudine (AZT), as well as those receiving highly active antiretroviral therapy (HAART) in conjunction with AZT, demonstrate a greater likelihood of resolving neutropenia compared to individuals who are not receiving any form of antiretroviral treatment [36, 37]. Furthermore, various studies have demonstrated that administering Granulocyte Colony-Stimulating Factor (G-CSF) or GM-CSF can effectively counteract myelosuppression, alleviate neutropenia in HIV-infected patients, and substantially reduce the occurrence of severe neutropenia, as well as the rates of bacterial infections and mortality [7, 38, 39].Therefore, early identification and treatment of neutropenia is very important.

Our study has several limitations. First, because all participants underwent bone marrow aspiration, the incidence of neutropenia observed in this cohort may not accurately reflect its prevalence in the entire HIV population. Second, we did not include the patients‘viral load, so their disease status remains unclear. Finally, we performed only statistical analyses of clinical data and did not carry out experimental validation, which we plan to conduct in future research.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

The authors would thank the patients from Zhongnan Hospital of Wuhan University who participated in the study.

Funding

This work was supported by the Zhongnan Hospital of Wuhan University discipline construction platform project [grant number 202021], Zhongnan Hospital of Wuhan University Science, Technology and Innovation Cultivation Fund [grant number ZNLH201902].

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Authors and Affiliations

  1. Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China

    Pengpeng Li, Xiaoyan Lv, Hui Shen, Jiamin Fang, Mingrui Wei, Xiaoyan Liu & Fuling Zhou

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  1. Pengpeng Li
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  2. Xiaoyan Lv
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  3. Hui Shen
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Contributions

All authors performed the research, Pengpeng Li collecting and analyzing the data and writing the paper, Fuling Zhou and Xiaoyan Liu designing the research study, Hui Shen providing the typical morphological changes in bone marrow cells and Xiaoyan Lv, Jiamin Fang, Mingrui Wei collecting and analyzing the data.

Corresponding authors

Correspondence to Xiaoyan Liu or Fuling Zhou.

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Ethics approval and consent to participate

The Zhongnan Hospital Ethics Committee of Wuhan University gave its approval to the study (2021006 K).

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The authors declare no competing interests.

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Li, P., Lv, X., Shen, H. et al. Associated factors and prognostic implications of neutropenia in individuals with HIV/AIDS. Virol J 22, 6 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12985-025-02624-x

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Virology Journal

ISSN: 1743-422X