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Severe pneumonia complicated by hemophagocytic lymphohistiocytosis in adults: a retrospective and exploratory clinical analysis
1Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
*Corresponding Author(s):zhangling1702@126.com (Ling Zhang); shaomin@ahmu.edu.cn (Min Shao)
† These authors contributed equally.
| History | Submitted: 20 August 2024 | Accepted: 05 December 2024 | Published: 08 March 2025 |
| Copyright: | ©2025 The Author(s). Published by MRE Press. |
Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening complication that can arise in adults with severe pneumonia (SP). This retrospective study analyzed the clinical characteristics, diagnostic approaches and treatment outcomes of adult patients diagnosed with SP complicated by HLH. Methods: The clinical data of 9 related adult patients were collected from the Department of Critical Care Medicine and analyzed. Results: The mean age of the patients was 41.11 ± 13.02 years, with 88.9% (8/9) being male. Comorbidities included post-renal transplantation, lymphoma, pregnancy, hepatitis E, syphilis and hypertension. The observed 28-day mortality rate was 22.2% (2/9), while the 60-day to 1-year mortality rates were both 77.8% (7/9). The etiological agents responsible for SP included bacteria (16%), viruses (52%), fungi (28%) and chlamydia (4%). Chest computed tomography revealed bilateral multiple exudative lesions. All patients met the 2004 HLH diagnostic criteria and had a mean HScore of 246.78 ± 44.11 and median ferritin level of 2828 µg/L (Inter Quartile Range (IQR) 2284–5152). Bone marrow cytology revealed mononuclear-phagocytic histiocytes in 8 of 9 patients. Lymphocyte subpopulations, including total lymphocyte count, cluster of differentiation (CD)4+ and CD8+ cells, were found to be significantly reduced (p < 0.01), while serum levels of interleukin (IL)-6 and IL-8 were markedly elevated (p < 0.001). Therapeutic interventions included targeted anti-infective treatment, with glucocorticoids administered to 5 patients, low-dose etoposide to 4 patients, intravenous immunoglobulin to 7 patients, and plasma exchange in 6 patients. Despite these interventions, mortality remained high. Conclusions: Routine monitoring of HLH diagnostic indicators in patients with SP is crucial, and anti-infective and supportive therapies, as well as immunosuppressive and cytotoxic agents, may offer potential benefits for critically ill patients.
Cite this article
Ling Zhang, Qi-Gang Yang, Min Shao. Severe pneumonia complicated by hemophagocytic lymphohistiocytosis in adults: a retrospective and exploratory clinical analysis. Signa Vitae. 2025; 21(3): 36-45. doi: 10.22514/sv.2025.034
1. Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening complication that can occur in adults with severe pneumonia (SP) and may significantly increase their mortality risks [1, 2]. Despite its clinical significance, the occurrence of HLH in adults with SP remains poorly studied, posing challenges in understanding its effective treatment and prognosis.
SP is a significant global health issue caused by progressive lung tissue inflammation due to various pathogens [3]. It has been associated with organ dysfunction and life-threatening conditions. The mortality rates for SP in adults range from 25% to 50% [4], with even higher rates of 50%–65% reported for critically ill patients with severe coronavirus disease 2019 (COVID-19) requiring intensive care unit (ICU) admission [5].
HLH is characterized by dysregulated immune responses resulting from excessive activation and proliferation of lymphocytes, macrophages and monocytes [6], which can lead to uncontrolled inflammation and the release of large quantities of pro-inflammatory cytokines. HLH is classified as either primary (pHLH), which is genetically inherited, or secondary (sHLH), which is triggered by infections, malignancies or autoimmune conditions [7]. The diagnosis of HLH in critically ill patients, particularly in the ICU, can be challenging due to its clinical similarity to other inflammatory conditions, such as sepsis. To address this diagnostic challenge, Fardet et al. [8] developed the HScore, a tool for estimating the likelihood of sHLH in patients.
This study aims to retrospectively analyze the clinical characteristics, diagnostic approaches, and treatment outcomes of adult patients with SP complicated by sHLH. By improving our understanding of this condition, the study seeks to enhance management strategies and improve prognosis in critically ill patients.
2. Materials and methods
2.1 Study population
This study comprised 9 adult patients diagnosed with SP (including both community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP)) complicated by sHLH admitted to the Department of Critical Care Medicine at the First Affiliated Hospital of Anhui Medical University between February 2020 and May 2022. This study was conducted in accordance with ethical standards for medical research and received approval from the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (approval number: Quick-PJ2022-06024).
2.1.1 Diagnostic criteria for SP
The diagnosis of SP in adults was based on the 2007 Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) criteria [9]. The definition includes the following: Major criteria: ① Requirement for invasive mechanical ventilation; ② Septic shock necessitating vasopressor support. Minor criteria: ① Respiratory rate ≥30 breaths/min; ② Arterial partial pressure of oxygen (PaO2)/Fraction of inspired oxygen (FiO2) ratio ≤250 mmHg; ③ Multilobar infiltrates on imaging; ④ Confusion or disorientation; ⑤ Uremia (blood urea nitrogen level ≥20 mg/dL); ⑥ Leukopenia (white blood cell count <4 × 109/L); ⑦ Thrombocytopenia (platelet count <100 × 109/L); ⑧ Hypothermia (core temperature <36 °C); ⑨ Hypotension requiring aggressive fluid resuscitation. For a diagnosis of SP, patients had to meet at least one major criterion or three minor criteria.
2.1.2 Diagnostic criteria for HLH
The diagnosis of HLH was based on the revised criteria established by the International Histiocyte Society in 2004 [7]. A diagnosis of HLH could be confirmed if one of the following conditions was met: ① A molecular diagnosis consistent with HLH; ② Fulfillment of at least five of the following eight clinical and laboratory criteria: (A) Initial diagnostic criteria: fever; splenomegaly; cytopenias affecting at least two of three blood cell lineages: Hemoglobin <90 g/L (in infants <4 weeks: hemoglobin <100 g/L), platelets <100 × 109/L, and neutrophils <1.0 × 109/L; Hypertriglyceridemia (fasting triglycerides ≥3.0 mmol/L or ≥265 mg/dL) and/or hypofibrinogenemia (fibrinogen ≤1.5 g/L); Hemophagocytosis observed in bone marrow, spleen or lymph nodes without evidence of malignancy; (B) New diagnostic criteria: Decreased or absent natural killer (NK) cell activity, as per local laboratory reference; Ferritin levels ≥500 mg/L; Soluble CD25 (i.e., soluble IL-2 receptor) ≥2400 U/mL.
2.2 Data collection
Clinical data, laboratory findings, imaging results, therapeutic interventions and outcomes of the study population were retrospectively collected. All test results were obtained within 72 hours of hospitalization and provided by the Department of Medical Laboratory and Imaging at the First Affiliated Hospital of Anhui Medical University.
2.2.1 Basic clinical information
Data collected included gender, age, comorbidities, oxygenation index (OI) at ICU admission, primary etiological factors and their detection methods, use of vasoactive drugs, mode of respiratory support, disease severity score and duration of invasive mechanical ventilation (IMV).
2.2.2 Chest imaging data
Chest imaging was performed using either X-ray (Digital Radiography Imaging System, MobiEye 700T, Mindray healthcare, Shenzhen, China) or computed tomography (CT) plain scan (GE Revolution 256-row wide-body detector CT, GE healthcare, Fairfield, CT, USA). The imaging data were automatically transmitted to a computer workstation for visualization and analysis.
2.2.3 Diagnosis and treatment of sHLH
Data related to the diagnosis and treatment of sHLH included the number of diagnostic criteria met, HScore values, and therapeutic interventions. The HScore, which calculates a cumulative score from nine variables, was used to assess the probability of HLH (https://saintantoine.aphp.fr/score/) [10]. Therapeutic measures recorded included targeted anti-infection treatment, glucocorticoids, etoposide, intravenous immunoglobulin (IVIG) and plasma exchange.
2.2.4 Cellular immune function
Cellular immune function was evaluated through the following parameters: (1) Neutrophil count: Assessed using automated hematology analyzers (XN-9000 Series, Sysmex, Kobe, Japan); (2) Lymphocyte subsets and ratios: Determined using clinical flow cytometry (BD FACSCanto™); (3) Cytokine levels: Measured using a multiplex bead-based flow fluorescent immunoassay (RAISECARE). All tests were performed according to the manufacturer’s protocols and standardized procedures.
2.2.5 Follow up
The prognosis of all patients was assessed through follow-up at 28 days, 60 days and 1 year post-hospitalization. Follow-up was conducted by trained professionals via telephone interviews.
2.3 Statistical analysis
The statistical analyses were conducted using SPSS 23.0 software (IBM, Armonk, NY, USA). Qualitative data were expressed as absolute values. The Shapiro-Wilk Test was used to determine whether quantitative data were normally distributed. For normally distributed, the data were described as mean ± standard deviation (x̄ ± s), and comparisons between two groups were made using the independent student t-test; otherwise the data were described as median (P25, P75), and the differences between two groups were expressed using the Mann-Whitney U test. Missing quantitative data were replaced by adjacent linear trends. p < 0.05 was considered statistically significant.
3. Results
3.1 Demographic characteristics and basic clinical information
This study included 9 adult patients with SP complicated by sHLH, comprising 8 males and 1 female. The mean age of the patients was 41.11 ± 13.02 years, the mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 22.67 ± 4.10, and the mean Sequential organ failure assessment (SOFA) score was 11.78 ± 1.64, as detailed in Table 1.
| Number | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 |
| Age (yr) | 50 | 45 | 27 | 36 | 31 | 46 | 33 | 69 | 33 |
| Gender | Male | Male | Female | Male | Male | Male | Male | Male | Male |
| Complication | Renal transplantation | Syphilis Hypertension | Pregnant | Renal transplantation | Renal transplantation | Lymphoma | Renal transplantation | Hepatitis E | Renal transplantation |
| Origin of SP | CAP | CAP | CAP | HAP | CAP | HAP | CAP | HAP | CAP |
| OI (mmHg) | 102.0 | 46.7 | 68.0 | 88.1 | 94.8 | 52.9 | 105.0 | 142.2 | 144.6 |
| Main etiology | EBV CMV PCP SM | AB HPVB19 HSV1 | Chlamydia psittaci | PAE EBV CMV Mucor | PCP CMV TTV | PAE EBV | PCP CMV BKV | Aspergillus CMV EBV | Mucor Aspergillus |
| Detection method | BALF mNGS + DNA | BALF + Blood mNGS | BALF + Blood mNGS | BALF mNGS + DNA | BALF mNGS | BALF + Blood mNGS | BALF mNGS + DNA | BALF mNGS + DNA | BALF + Blood mNGS |
| Vasopressor | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No |
| Respiratory support | IMV NIPPV | VV-ECMO IMV | IMV HFNO | IMV | NIPPV HFNO | IMV | HFNO IMV | IMV | IMV HFNO |
| APACHE II | 29 | 24 | 21 | 24 | 17 | 17 | 27 | 24 | 21 |
| SOFA | 10 | 14 | 11 | 12 | 10 | 10 | 13 | 14 | 12 |
| CPIS | 8 | 7 | 11 | 9 | 8 | 9 | 8 | 10 | 11 |
| MV days (d) | 27 | 57 | 28 | 5 | 0 | 18 | 30 | 11 | 4 |
| Abbreviations: OI: Oxygenation index; APACHE II: Acute Physiology and Chronic Health Evaluation II; SOFA: Sequential organ failure assessment; CPIS: Clinical pulmonary infection score; EBV: EB virus; CMV: cytomegalovirus; PCP: Pneumocystis carinii; HPVB19: human parvovirus B19; HSV1: herpes simplex virus 1; SM: Serratia marcescens; AB: Acinetobacter baumannii; PAE: Pseudomonas aeruginosa; TTV: human parvovirus; BKV: BK virus; BALF: bronchoalveolar lavage fluid; mNGS: macro genomic sequencing; NIPPV: non-invasive positive pressure ventilation; VV-ECMO: veno-venous extracorporeal membrane oxygenation; HFNO: nasal high flow oxygen therapy; SP: severe pneumonia; CAP: community-acquired pneumonia; HAP: hospital-acquired pneumonia; IMV: invasive mechanical ventilation; MV: mechanical ventilation. |
Regarding comorbidities, 5 had undergone kidney transplantation, while 1 had lymphoma. Three patients (3/9) presented with syphilis and hypertension, pregnancy and hepatitis E, respectively. At ICU admission, the mean OI was 93.81 ± 34.83 mmHg. Of the 9 patients, 1 required VV-ECMO (veno-venous extracorporeal membrane oxygenation), 1 received non-invasive respiratory support, and the remaining 7 patients were managed with IMV. The mean duration of IMV was 20.00 ± 17.85 days. The demographic characteristics and pathological findings of the nine patients are summarized in Fig. 1.
Fig. 1.Etiology of severe pneumonia in the 9 investigated patients. (A) Detailed etiology of severe pneumonia. (B) Etiological classification of severe pneumonia. EBV: EB virus; CMV: cytomegalovirus; HSV1: herpes simplex virus 1; BKV: BK virus; TTV: human parvovirus; HPVB19: human parvovirus B19; PCP: Pneumocystis carinii.
3.2 Chest imaging findings
Chest imaging revealed multiple exudative lesions in both lungs of all 9 patients, which appeared as patchy, solid, ground-glass, lattice-like, nodular or cavernous shadows, depending on the underlying etiology. One patient presented with pneumothorax, and 6 exhibited a small amount of pleural effusion. Representative chest CT scans are shown in Fig. 2, highlighting different etiologies: PCP (Pneumocystis carinii) combined with CMV (cytomegalovirus), Aspergillus fumigatus co-infection with CMV, and Chlamydia psittaci.
Fig. 2.Chest CT findings. (A,B) In the case of PCP combined with CMV, the chest CT scan (lung window) revealed patchy and reticular exudation in both lungs, predominantly in the upper lobes. (C,D) For Aspergillus fumigatus co-infection with CMV, the chest CT scan (lung window) showed consolidation in the upper left lung with an air crescent sign. Additionally, patchy ground-glass opacities were observed in the right lung, accompanied by bilateral pleural effusion. (E,F) For Chlamydia psittaci, the chest CT scan (lung window) demonstrated patchy shadows and consolidation in both lungs, with a bronchial inflation sign present.
3.3 Diagnosis, treatment and prognosis of sHLH
All 9 patients met the diagnostic criteria for HLH as outlined in the 2004-HLH guidelines. The mean HScore was 246.78 ± 44.11, and the median ferritin level was 2828 µg/L (IQR 2284–5152) (Fig. 3). Of note, Patient 4 did not undergo ferritin testing.
Fig. 3.The HLH standard numbers, HScore and serum ferritin level of the investigated patients. (A) HLH standard number and Hscore of each patient. (B) Serum ferritin level of each patient. HLH: Hemophagocytic lymphohistiocytosis.
All patients underwent bone marrow aspirations. The morphological examination revealed a state of active bone marrow proliferation, accompanied by the presence of mononuclear and phagocytic histiocytes in 8 patients (Fig. 4).
Fig. 4. Monocyte-phagocytic cells in bone marrow cytological smear. Morphological examination of bone marrow cells demonstrated the presence of mononuclear and phagocytic histiocytes. (A) Monocytes phagocytosing platelets and mature erythrocytes. (B) Monocytes phagocytosing lymphocytes, neutrophils and mature erythrocytes. Staining was performed using Wright-Giemsa, captured at 10 × 100 magnification.
All 9 patients received targeted anti-infection treatments. Additional therapies included glucocorticoids (administered to 5 patients), low-dose etoposide (VP-16, administered to 4 patients), IVIG (administered to 7 patients), and plasma exchange (performed in 6 patients). The detailed treatment regimens are outlined in Table 2.
| Treatments | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 |
| Anti-infection | Ganciclovir | Tigecycline Ganciclovir | Doxycycline | Amphotericin B liposome | SMZ Ganciclovir | Meropenem | SMZ Ganciclovir | Voriconazole Ganciclovir | Amphotericin B liposome |
| Glucocorticoid | MP | No | DXM | DXM | MP | MP | No | No | No |
| VP-16 | No | No | Yes | Yes | Yes | No | Yes | No | No |
| IVIG | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| PE | Yes | No | Yes | Yes | No | Yes | Yes | Yes | No |
| VP-16: etoposide; IVIG: intravenous immunoglobulin; SMZ: sulfamethoxazole; PE: plasma exchange. |
In terms of prognosis, the 28-day mortality rate was 22.2% (2/9), with Patients 8 and 9 succumbing to the disease within this period. Long-term follow-up revealed that only two patients (Patients 3 and 5) survived beyond 60 days and 1 year, corresponding to a 1-year mortality rate of 77.8% (7/9). Notably, Patient 3 did not exhibit recurrence of sHLH during a subsequent successful pregnancy occurring one year after hospitalization.
3.4 Cellular immune function
As shown in Table 3, lymphocyte counts and their subpopulations were markedly reduced across all patients. The median total lymphocyte count was 0.25 × 109/L (IQR: 0.13–0.45 × 109/L), the CD4+ T cell count was 51 cells/µL (IQR: 43–184 cells/µL), and the CD8+ T cell count was 72 cells/µL (IQR: 45–131.5 cells/µL). The CD4+/CD8+ ratio was 1.23 ± 0.95, and the NK cell count was 29 cells/µL (IQR: 17–300 cells/µL). The total lymphocyte count, as well as CD4+ and CD8+ T cell counts, were significantly below the lower limit of the normal range (p < 0.01).
| Number | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | |
| Neutrophil and lymphocyte subsets count | ||||||||||
| NEUT (109/L) (1.8∼6.3) | 0.11 | 2.55 | 11.02 | 3.91 | 1.23 | 1.34 | 1.74 | 11.28 | 0.02 | |
| LY (109/L) (1.1∼3.2) | 0.11 | 0.34 | 1.30 | 0.22 | 0.25 | 0.32 | 0.15 | 0.55 | 0.11 | |
| CD3+ (cells/µL) (690∼2540) | — | 285 | 647 | 98 | 123 | 158 | 112 | 279 | 82 | |
| CD4+ (cells/µL) (410∼1590) | 84 | 184 | 364 | 36 | 27 | 44 | 43 | 79 | 51 | |
| CD8+ (cells/µL) (190∼1140) | 27 | 88 | 238 | 68 | 72 | 80 | 59 | 175 | 31 | |
| CD4+/CD8+ (0.9∼2.1) | 3.11 | 2.10 | 1.53 | 0.52 | 0.38 | 0.54 | 0.73 | 0.45 | 1.68 | |
| NK (cells/µL) (78∼756) | — | 97 | 300 | 9 | 7 | 570 | 17 | 29 | 28 | |
| CD45+ (cells/µL) | — | 422 | 1111 | — | 135 | 737 | 135 | 393 | 123 | |
| NLR | 1.00 | 7.50 | 8.47 | 17.77 | 4.92 | 4.19 | 11.60 | 20.51 | 0.18 | |
| Serum cytokine level (pg/mL) | ||||||||||
| IL-1β (≤12.4) | 35.22 | 1.77 | 27.28 | — | <5.00 | 35.21 | 17.37 | 14.72 | 9.09 | |
| IL-6 (≤5.4) | 770.00 | 9929.15 | 39.00 | 2360.00 | 10.40 | 42.98 | 9261.89 | 194.62 | 9153.33 | |
| IL-8 (≤20.6) | 1267.00 | 318.79 | 158.00 | — | 61.60 | 282.17 | 136.61 | 285.40 | 1492.04 | |
| IL-10 (≤12.9) | 25.09 | 18.86 | <5.00 | 143.00 | 13.28 | 3130.65 | 2.64 | 19.87 | 4.74 | |
| TNF-α (≤16.5) | 48.40 | 2.78 | 33.37 | 1.13 | 75.29 | 20.70 | 2.42 | 2.94 | <1.58 | |
| IFN-γ (≤23.1) | — | 6.44 | — | 26.90 | — | >10,000.00 | 418.91 | 13.36 | 83.58 | |
| Remarks: NEUT: neutrophil count; LY: lymphocyte count; NLR: neutrophil count/lymphocyte count ratio; CD: cluster of differentiation; NK: natural killer; IL: interleukin; TNF-α: tumor necrosis factor α; IFN-γ: interferon γ. |
Moreover, the levels of serum cytokines (IL-1β, IL-6, IL-8, IL-10, tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ)) exhibited varying degrees of alteration. Among them, the serum levels of IL-6 and IL-8 were significantly elevated, with IL-6 measured at 770 (40.99, 9207.61) pg/mL and IL-8 measuring 285.40 (42.98, 9153.33) pg/mL, both exceeding the upper limit of the normal range (p < 0.001).
4. Discussion
SP in adults is a severe condition of acute respiratory infection and represents a significant global health challenge for healthcare systems. HLH is characterized by excessive inflammatory responses, leading to the benign proliferation of tissue cells and widespread phagocytosis of hematopoietic cells [7]. sHLH is more commonly observed in adults and is often triggered by immune system activation due to underlying conditions such as infections [11]. When SP is complicated by sHLH, it becomes a fatal condition, further complicating the effective management of critically ill patients [12]. However, there is limited research addressing SP complicated by sHLH in adult ICU populations.
Mortality rates in adult patients with sHLH admitted to the ICU are alarmingly high. Lachmann et al. [13] reported a mortality rate of 44%, while Nyvlt et al. [14] observed a comparable rate of 43.3%. Meng et al. [10] found that mortality among COVID-19 patients suspected of being sHLH-positive was significantly higher than in the suspected sHLH-negative group (100% vs. 34.77%, p < 0.001). Additionally, the 1-year survival rate for HLH patients has been reported at 50%, highlighting the urgent need for advancements in HLH treatment strategies [15]. In our study, the mortality rates were 22.2% at 28 days and 77.8% at 60 days to 1 year post-hospitalization. These findings underscore the severity of sHLH in the context of SP. The high mortality observed in our study may be influenced by several factors, including the small study population, elevated APACHE II and SOFA scores, and the severity of the underlying trigger conditions.
Shi et al. [16] identified male gender as a risk factor for poor prognosis in severe COVID-19 patients, with literature confirming male predominance in HLH [11]. A nationwide study in England by West et al. [15], which analyzed HLH cases from 2003 to 2018, reported a higher prevalence of males (56.51% vs. 43.49%). Furthermore, the study highlighted that one-year survival rates for HLH varied significantly by gender, with males exhibiting worse outcomes compared to females [15]. In our study, 88.9% of the patients were male (8 out of 9), suggesting that gender may be a potential risk factor for poor prognosis in SP complicated by sHLH. However, confirmation of this association requires further investigation using larger sample size cohorts.
The pathogens responsible for SP are influenced by factors such as environmental exposure, local epidemiology and individual immune status. Previous studies have demonstrated that bacteria are the most frequent pathogens in severe respiratory infections among immunosuppressed patients, followed by RNA and DNA viruses and invasive fungi [17, 18]. Ren et al. [19] described 18 cases of cytomegalovirus (CMV) pneumonia in patients with inflammatory bowel disease, with half of the cases complicated by sHLH. Bichon et al. [20] conducted a retrospective analysis of a large cohort of ICU patients with HLH, identifying infections as the primary trigger. The implicated pathogens included extracellular bacteria, fungi, Epstein-Barr virus (EBV), influenza virus, COVID-19 and mycobacteria [20]. Despite varying etiologies and specific treatments, the mortality rate of ICU-related HLH remained high at 57% [20]. In our study, the most common pathogens included DNA viruses (e.g., EBV, HSV (herpes simplex virus), CMV) and fungi (e.g., PCP), generally consistent with previous studies.
Viral infections are particularly prevalent in severely immunosuppressed patients with T-cell deficiencies [21, 22]. Griffin et al. [23] reviewed the occurrence of HLH in adults with severe combined immunodeficiency and in those undergoing chemotherapy or immunosuppressive therapy for inflammatory diseases. They identified intracellular pathogens, particularly viruses, as the predominant infectious triggers for HLH [23]. In this study, 6 of the 9 cases were immunosuppressed, 5 of whom were post-renal transplant recipients. While only a few cases of HLH secondary to viral infection following renal transplantation have been reported in literature [24, 25], and no large-scale studies have systematically explored this association in adults. Based on our findings, it is plausible to speculate that the immunosuppressive state following renal transplantation may represent a risk factor for SP complicated by sHLH. Additionally, 1 pregnant patient in our study, who presented with SP complicated by sHLH involving the central nervous system, was infected with Chlamydia psittaci. To our knowledge, no prior cases of Chlamydia psittaci infection in a pregnant patient leading to sHLH with central nervous system involvement have been documented. We hypothesize that the Chlamydia psittaci infection and pregnancy status may act as independent risk factors for sHLH and central nervous system involvement in such cases.
HLH is characterized by an uncontrolled inflammatory response mediated by hypercytokinemia, with elevated levels of cytokines such as IL-1β, IL-6, IL-18, IFN-γ and TNF-α, driven by dysregulated cellular immune responses [26]. T cells, particularly CD4+ and CD8+ subsets, are essential for modulating and suppressing excessive innate immune activation [27]. In severe COVID-19, the depletion of CD4+ and CD8+ T cells has been associated with increased inflammatory responses, cytokine storm activation, and worse clinical outcomes [28]. In our study, serum levels of IL-6 and IL-8 were markedly elevated, significantly exceeding the upper limit of the normal range. Concurrently, the total lymphocyte count, as well as CD4+ and CD8+ T cell counts, were significantly below the normal lower limit. These findings suggest that the patients were experiencing uncontrolled cellular immunity driven by severe infections, potentially influenced by underlying viral and fungal infections and immunosuppressive states. Moreover, the 2 survivors in our cohort had lymphocyte subset counts that were generally within the normal range.
The clinical manifestations and organ dysfunction caused by severe infections can closely resemble those of HLH, potentially leading to an underestimation of sHLH incidence in ICU settings. Due to the common presence of severe leukopenia in these patients, NK cell count and functional assays are not routinely recommended [8]. However, ferritin levels ≥3095 µg/L have demonstrated a sensitivity of 100% and specificity of 82.6% for diagnosing sHLH in ICU patients. In addition to the HLH-2004 criteria, the HScore has proven to be a valuable diagnostic tool, with an HScore >169 yielding sensitivity and specificity of 93% and 86%, respectively [8]. Furthermore, combining the HLH-2004 criteria with an HScore >168 has been shown to provide optimal diagnostic accuracy [29]. High HScore values may also predict both the diagnosis and mortality risk associated with HLH [10, 30]. Consistent with these findings, all nine patients in our study met at least five HLH-2004 criteria, and their HScore values were ≥158, aligning with previous studies.
The treatment of sHLH generally encompasses three main strategies [7, 26]: controlling the underlying disease, managing excessive inflammation, and providing symptomatic supportive care. Hansen et al. [31] reported successful outcomes using ruxolitinib to treat four patients with sHLH. In our study, all patients received targeted anti-infective therapies and comprehensive supportive care, with 5 also treated with glucocorticoids. Although etoposide (VP-16) has shown potential in treating HLH secondary to infection by inhibiting macrophage activation, restoring immune homeostasis, and clearing infected cells, only four patients in this cohort received low doses of the drug. Notably, neither of the 2 surviving patients experienced recurrence during the 1-year follow-up, suggesting the potential efficacy of these treatments. Nevertheless, individualized treatment remains essential for critically ill patients. For patients unable to tolerate glucocorticoids or cytotoxic therapies, alternative strategies such as IVIG, plasma exchange [32], or cytokine adsorption may be beneficial by mitigating excessive inflammatory cytokines [33]. In this study, 7 patients received IVIG, and 6 underwent plasma exchange. However, these interventions did not significantly improve survival outcomes, indicating the need for further investigation into the effectiveness of these treatments for sHLH.
This study has several limitations. First, it is a single-center study with a small sample size, which may limit the generalizability of the findings. Validation of the results through larger sample sizes and multicenter studies is warranted. Second, the retrospective design relied on data collected from electronic medical records, which may have introduced minor gaps or inconsistencies in the data.
5. Conclusions
In conclusion, sHLH is a severe complication of adult SP characterized by rapid progression, high mortality and poor prognosis. Early monitoring of HLH-related indicators, including the use of HScore, could be essential for the timely detection and confirmation of sHLH in adult SP patients, particularly those with viral or other specific pathogenic infections. In addition to targeted anti-infective and supportive therapies, immunosuppressive and cytotoxic medications may play an important role in severe cases by mitigating cytokine storms and improving clinical outcomes. Future research should aim to further elucidate the pathophysiological mechanisms underlying sHLH and explore more effective therapeutic options to improve the prognosis of these critically ill patients.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.
Author contributions
LZ—Investigation, material preparation, data collection and writing-original draft were performed. QGY—Methodology and formal analysis were performed. LZ, MS—The Writing-review draft of the manuscript was written. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. All authors contributed to the study conception and design.
Ethics approval and consent to participate
This study was conducted in accordance with ethical standards for medical research and received approval from the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (approval number: Quick-PJ2022-06024). Written informed consent was obtained from a legally authorized representative for anonymized patient information to be published in this article.
Acknowledgment
Not applicable.
Funding
This work was supported by the Provincial Natural Science Foundation of Education Department of Anhui (Key project) (Grant No. KJ2021A0309) and Anhui Medical University research fund project (Grant No. 2021xkj151).
Conflict of interest
The authors declare no conflict of interest.
