ABSTRACT
Background
Haemophagocytic lymphohistiocytosis (HLH) is a life‐threatening hyperinflammatory syndrome that may occur in people living with HIV/AIDS (PLWHA), often triggered by opportunistic infections such as disseminated histoplasmosis (DH). The substantial overlap in clinical and laboratory features between HLH and DH complicates timely diagnosis.
Objectives
To describe HLH among PLWHA with DH and compare clinical, laboratory and outcome characteristics between patients with and without HLH.
Patients/Methods
A retrospective observational study was conducted at São José Hospital of Infectious Diseases, Fortaleza, Brazil, between March 2023 and June 2024. Hospitalised PLWHA with DH were evaluated for HLH based on the presence of ≥ 3 HLH‐2004 criteria and an H‐Score ≥ 169. Baseline clinical, laboratory and outcome parameters were compared between patients with and without HLH.
Results
Among 61 patients diagnosed with DH, 11 (18.0%) met the study criteria for HLH. Patients with HLH were more likely to present with hepatomegaly (p = 0.036), haemoptysis (p = 0.030) and lower platelet counts (p = 0.029). In‐hospital mortality was significantly higher among patients with HLH (54.5% versus 18.0%; p = 0.019). These patients more frequently required renal replacement therapy (p = 0.028) and intensive care unit admission (p = 0.048). Kaplan–Meier analysis with log‐rank testing demonstrated significantly reduced in‐hospital survival among patients with HLH (p = 0.015).
Conclusions
HLH represents a severe complication in PLWHA with DH and is associated with increased mortality and greater need for intensive care. Early recognition and use of adjunctive diagnostic tools may facilitate timely management and improve clinical outcomes.
Keywords: acquired immunodeficiency syndrome, disseminated histoplasmosis, haemophagocytic lymphohistiocytosis, haemophagocytic syndrome, HIV infection, prognosis
1. Introduction
Histoplasmosis is an endemic mycosis caused by the dimorphic fungus Histoplasma capsulatum [1]. Transmission occurs primarily through inhalation of fungal spores present in acidic, humid, nitrogen‐rich soils contaminated with bat or bird excrement [2]. In immunocompromised individuals, particularly people living with HIV/AIDS (PLWHA), histoplasmosis often presents as disseminated histoplasmosis (DH), a severe systemic disease. In some settings, DH has been reported as the most common AIDS‐defining illness, with higher incidence and mortality among patients with CD4+ T‐cell counts below 150 cells/μL [3].
Haemophagocytic lymphohistiocytosis (HLH), also known as haemophagocytic syndrome, is a life‐threatening condition characterised by excessive cytokine release and uncontrolled activation of cytotoxic lymphocytes and histiocytes, leading to a hyperinflammatory state and haemophagocytosis. HLH may be primary (genetic) or secondary to infections, autoimmune disorders, or malignancies [4]. Approximately half of the HLH cases in adults are infection‐related, with HIV and histoplasmosis accounting for 15.6% and 1.6% of cases, respectively [5].
In adults, diagnosis requires either identification of a genetic defect or fulfilment of at least five of eight established criteria: fever, splenomegaly, cytopenias in ≥ 2 lineages, hyperferritinemia, hypertriglyceridemia and/or hypofibrinogenemia, reduced or absent natural killer cell activity, elevated soluble CD25, and evidence of haemophagocytosis in bone marrow, spleen, or lymph nodes [6, 7]. The H‐Score is a validated tool estimating HLH probability, ranging from < 1% (≤ 90 points) to > 99% (≥ 250 points), based on clinical features (immunosuppression, fever, hepatomegaly, splenomegaly) and laboratory data (cytopenias, ferritin, triglycerides, fibrinogen, aspartate aminotransferase [AST] and bone marrow haemophagocytosis) [8].
The clinical manifestations of DH frequently overlap with those of HLH, and both conditions may coexist [9]. Features such as fever, splenomegaly, cytopenias and hyperferritinemia are common to both syndromes, complicating differentiation [10]. HLH has been reported in PLWHA with or without disseminated infections and is recognised as a complication of acute DH regardless of HIV status [10, 11, 12].
This study aimed to describe HLH in PLWHA with DH and to compare their sociodemographic, clinical, laboratory and outcome characteristics with those of patients without HLH.
2. Methods
2.1. Study Design
A retrospective observational study was conducted between March 2023 and June 2024 at São José Hospital of Infectious Diseases (HSJ), a tertiary referral centre of the Brazilian Unified Health System (SUS) in Fortaleza, Ceará, Brazil. Patients were followed throughout hospitalisation until discharge or in‐hospital death, whichever occurred first.
2.2. Study Population
Eligible participants were PLWHA aged ≥ 18 years, hospitalised with probable or proven DH. Patients who provided informed consent were included in the study; those who declined were excluded. In cases where consent could not be obtained due to death before signing, treatment discontinuation, or relocation, a waiver of consent was granted by the institutional ethics committee. Patients were excluded only if clinical or laboratory data essential for outcome analysis were unavailable.
2.3. Diagnostic Criteria
HIV infection was confirmed using a fourth‐generation immunoassay followed by a rapid immunoblot. Patients were considered to have proven DH if they met at least one of the following criteria: visualisation of H. capsulatum‐like yeasts in peripheral blood (PB), buffy coat (BC), bone marrow aspirate (BMA), or another sterile site; or isolation of H. capsulatum in cultures of peripheral blood, BC, BMA, or another sterile site. Patients with a compatible clinical presentation (fever and/or respiratory symptoms) and a positive urinary antigen test result were considered to have probable DH [13].
For the purposes of this study, HLH was diagnosed in patients who fulfilled at least three of the evaluated HLH‐2004 criteria (fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia/hypofibrinogenemia, or haemophagocytosis in BMA) [6] together with an H‐Score ≥ 169, corresponding to a reported sensitivity of 93% and a specificity of 86% [8]. Because NK cell activity and soluble CD25 were not available, the six HLH‐2004 criteria were assessed. The H‐Score was calculated using the validated online tool (https://saintantoine.aphp.fr/score/). When variables required for score calculation were unavailable, the ‘unknown’ category was used whenever applicable. For ferritin values exceeding the assay's upper reporting limit (1500 ng/mL), results were classified conservatively according to the lowest applicable H‐Score category (‘strictly less than 2000 ng/mL’).
2.4. Severity Profile
The Histoplasma Fatality Score (HFS) assesses the risk of death from DH within 30 days, based on clinical (World Health Organization performance status scale, altered mental status, dyspnoea), laboratory (cytopenias in blood count, C‐reactive protein) and radiological parameters (chest X‐ray), with a maximum score of 12 [14]. HFS scores < 5 were associated with a negative predictive value of 97% (95% CI: 95%–99%) and a risk of death ≤ 5% within 30 days. Conversely, HFS scores ≥ 5 were associated with mortality ≥ 33% within 30 days. Although not formally validated in Brazil, the HFS was used to provide a standardised assessment of baseline severity.
2.5. Laboratory Procedures
Direct microscopy of BC, BMA and other samples was performed on panoptic fast‐stained smears. Blood cultures were processed using BD Bactec Myco/F Lytic flasks and incubated in BD Bactec Fx (Becton Dickinson, Franklin Lakes, NJ, USA). BC and BMA cultures were performed on Sabouraud and Mycosel media. The urinary antigen test used was the Histoplasma Urine Lateral Flow Assay (LFA) (MiraVista Diagnostic Laboratories, Indianapolis, Indiana, USA).
2.6. Data Collection
Sociodemographic, clinical and laboratory data were obtained through patient interviews and medical records. For the assessment of HLH criteria, the most extreme values recorded during hospitalisation were considered: the lowest levels of haemoglobin, neutrophils and platelets; the highest levels for triglycerides, ferritin and body temperature; and the lowest fibrinogen concentration.
Certain laboratory parameters (e.g., fibrinogen, ferritin and triglycerides) were not systematically collected for all patients, as test requests were made at the attending medical team's discretion. Missing data reflected the absence of test requests rather than attrition or follow‐up loss. No imputation procedures were performed. Analyses for each laboratory variable were conducted using complete‐case analysis, excluding patients without available measurements for the respective parameter. Cumulative exposure to amphotericin B was quantified as the total number of days of administration, aggregated across different formulations (deoxycholate, lipid complex and liposomal). For analytic purposes, days on each formulation were summed to provide a single measure of treatment duration.
2.7. Outcomes
The primary outcome was the presence of HLH during hospitalisation. Secondary outcomes included: acute kidney injury (AKI), defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria [15]; need for renal replacement therapy (RRT); mechanical ventilation; intensive care unit (ICU) admission; vasoactive drug use; and in‐hospital mortality (all‐cause).
2.8. Statistical Analysis
Categorical variables were expressed as counts and percentages. Fisher's exact test was used for 2 × 2 comparisons, whereas Pearson's chi‐squared test was applied for contingency tables larger than 2 × 2. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using exact methods. Continuous variables were expressed as medians with interquartile ranges (Q1–Q3) and compared between groups using the Mann–Whitney U test.
Ferritin levels were analysed as a dichotomous variable using a predefined cut‐off (> 1500 ng/mL), owing to the assay's upper reporting limit. Time‐to‐event analysis was performed using the Kaplan–Meier method to compare in‐hospital survival between patients with and without HLH. Time was defined as the number of days from hospital admission to the outcome, with death coded as the event and hospital discharge treated as censoring. Survival curves were compared using the log‐rank (Mantel–Haenszel) test.
All statistical analyses were performed using JASP software (Version 0.95.4; JASP Team, 2025). Two‐sided p‐values < 0.05 were considered statistically significant.
2.9. Ethical Statement
The authors confirm that the journal's ethical standards were upheld. The study was approved by the HSJ Research Ethics Committee (protocol no. 60380022.0.0000.5044).
3. Results
During the study period, 63 PLWHA with DH were hospitalised at HSJ. Two patients declined to provide informed consent; therefore, 61 individuals were included in the analysis. The study population was predominantly male (78.7%), with a median age of 40.0 (32.0–46.0) years. Eleven patients (18.0%) met diagnostic criteria for HLH during hospitalisation. Sociodemographic, epidemiological and clinical characteristics are summarised in Table 1.
TABLE 1.
Sociodemographic, epidemiological and clinical characteristics of patients with HIV/AIDS and DH with and without HLH (n = 61), HSJ, Fortaleza, Brazil, 2023–2024.
| Characteristic | Non‐HLH (n = 50) | HLH (n = 11) | p |
|---|---|---|---|
| Age | 40.5 (31.3–46.0) | 34.0 (32.0–46.0) | 0.841 |
| Male sex | 38 (76.0%) | 11 (90.9%) | 0.429 |
| Race/ethnicity | 0.313 | ||
| White | 5 (10.0%) | 0 (0.0%) | |
| Brown a | 41 (82.0%) | 11 (100.0%) | |
| Black | 4 (8.0%) | 0 (0.0%) | |
| Chronic non‐infectious comorbidities | 0.677 | ||
| DM or SAH | 2 (4.0%) | 0 (0.0%) | |
| Chronic kidney disease | 3 (6.0%) | 0 (0.0%) | |
| Nephrolithiasis | 2 (4.0%) | 0 (0.0%) | |
| Chronic pulmonary disease | 2 (4.0%) | 0 (0.0%) | |
| Coinfection during hospitalisation | |||
| Tuberculosis | 14 (28.0%) | 1 (9.1%) | 0.265 |
| Syphilis | 5 (10.0%) | 1 (9.1%) | 1.000 |
| Cryptococcosis | 2 (4.0%) | 2 (18.2%) | 0.146 |
| Hepatitis B | 2 (4.0%) | 1 (9.1%) | 0.455 |
| Visceral leishmaniasis | 1 (2.0%) | 0 (0.0%) | 1.000 |
| Cytomegalovirus infection | 2 (4.0%) | 1 (9.1%) | 0.455 |
| Epstein–Barr virus infection | 2 (4.0%) | 0 (0.0%) | 0.500 |
Abbreviations: DH, disseminated histoplasmosis; DM, diabetes mellitus; HLH, haemophagocytic lymphohistiocytosis; HSJ, São José Hospital; SAH, systemic arterial hypertension.
The term “brown” is used in Brazilian demographic classifications (“pardo”) and may refer to mixed‐race individuals.
On admission, disease severity, as assessed by the HFS, was higher among patients with HLH than among those without HLH (median 7.0 [6.5–9.5] versus 6.0 [5.0–7.0], p = 0.021). Notably, all patients with HLH had an HFS ≥ 5 (range 5–11), whereas the non‐HLH group included patients with lower scores (range 2–11).
Clinical signs and symptoms at admission are summarised in Table 2. Haemoptysis was rare, occurring in only two patients, both of whom developed HLH (2/11 vs. 0/50). Given the small number of events and complete separation between groups, effect estimates were not calculated to avoid unstable measures. No significant differences in body mass index (BMI) were observed between groups: median 18.1 kg/m2 (16.0–20.4) in the non‐HLH group versus 18.1 kg/m2 (16.6–19.3) in the HLH group (p = 0.861).
TABLE 2.
Clinical signs and symptoms of patients with HIV/AIDS and DH and association with HLH (n = 61), HSJ, Fortaleza, Brazil 2023–2024.
| Parameter | Non‐HLH (n = 50) | HLH (n = 11) | p |
|---|---|---|---|
| Fever | 46 (92.0%) | 11 (100.0%) | 1.000 |
| Weight loss (> 10.0% of BW) | 37 (74.0%) | 10 (90.9%) | 0.430 |
| Fatigue | 31 (62.0%) | 10 (90.9%) | 0.084 |
| Dyspnoea | 31 (62.0%) | 9 (81.8%) | 0.302 |
| Dry cough | 28 (56.0%) | 3 (27.3%) | 0.106 |
| Hepatomegaly | 19 (38.0%) | 8 (72.7%) | 0.036 |
| Diarrhoea | 17 (34.0%) | 4 (36.4%) | 1.000 |
| Nausea/vomiting | 14 (28.0%) | 5 (45.6%) | 0.294 |
| Splenomegaly | 15 (30.0%) | 7 (63.6%) | 0.079 |
| Chills | 14 (28.0%) | 2 (18.2%) | 0.711 |
| Lymphadenopathy | 14 (28.0%) | 4 (36.4%) | 0.717 |
| Productive cough | 15 (30.0%) | 4 (36.4%) | 0.726 |
| Night sweats | 6 (12.0%) | 0 (0.0%) | 0.580 |
| Chest pain | 4 (8.0%) | 0 (0.0%) | 1.000 |
| Jaundice | 2 (4.0%) | 1 (9.1%) | 0.455 |
| Haemoptysis | 0 (0.0%) | 2 (18.2%) | 0.030 |
Abbreviations: BW, body weight; DH, disseminated histoplasmosis; HLH, haemophagocytic lymphohistiocytosis; HSJ, São José Hospital.
No significant differences were observed in HIV viral load, CD4+ T‐cell count, or CD8+ T‐cell count between patients with and without HLH. The proportion of patients with ferritin levels > 1500 ng/mL was similar between groups: 9/10 (90.0%) with HLH and 21/27 (77.8%) without HLH (p = 0.647). Patients with HLH had significantly lower platelet counts than those without HLH (p = 0.029). Available laboratory measurements are indicated in Table 3.
TABLE 3.
Laboratory findings of patients with HIV/AIDS and DH and association with HLH (n = 61), HSJ, Fortaleza, Brazil, 2023–2024.
| Test (unit) | Non‐HLH (n = 50) | HLH (n = 11) | p |
|---|---|---|---|
| HIV viral load (copies/mL) |
803,400.0 (79,080.0–2,713,000.0) |
13,800.0 (877.0–1,080,000.0) |
0.155 |
| CD4+ T‐cells/mm3 | 46.0 (17.0–95.0) | 33.0 (17.5–59.0) | 0.241 |
| CD8+ T‐cells/mm3 | 403.5 (263.3–805.5) | 270.5 (149.3–798.0) | 0.383 |
| Haemoglobin (g/dL) | 9.3 (7.9–10.5) | 8.3 (7.9–9.8) | 0.493 |
| Leukocytes (/mm3) | 3315.0 (2025.0–4975.0) | 2200 (2100–2950) | 0.115 |
| Neutrophils (/mm3) | 2444 (1714–3963) | 2002 (1317–2776) | 0.162 |
| Platelets (/mm3) | 102,000.0 (64,750.0–175,300.0) | 52,000.0 (38,000.0–104,500.0) | 0.029 |
| CRP (mg/L) | 115.9 (62.7–153.9) | 141.4 (116.8–189.9) | 0.121 |
| Urea (mg/dL) | 37.7 (30.0–57.0) | 36.0 (34.5–54.5) | 0.714 |
| Creatinine (mg/dL) | 1.0 (0.7–1.3) | 1.1 (0.9–1.3) | 0.280 |
| AST (U/L) | 185.5 (63.9–361.8) | 264.0 (166.5–589.5) | 0.070 |
| ALT (U/L) | 60.0 (28.3–101.5) | 50.0 (36.5–113.0) | 0.593 |
| Triglycerides (mg/dL) a | 135.3 (104.0–200.0) | 207.5 (176.3–260.5) | 0.065 |
| Direct bilirubin (mg/dL) | 0.3 (0.1–0.5) | 0.9 (0.2–1.1) | 0.092 |
| Indirect bilirubin (mg/dL) | 0.4 (0.3–0.6) | 0.7 (0.4–1.0) | 0.059 |
| Albumin (g/dL) | 2.4 (2.0–2.9) | 1.7 (1.5–1.9) | 0.067 |
| Alkaline phosphatase (U/L) | 354.0 (107.0–542.0) | 171.5 (100.0–415.8) | 0.384 |
| GGT (U/L) | 125.9 (76.8–278.3) | 104.0 (53.0–354.3) | 0.878 |
| Lactate dehydrogenase (U/L) |
1511.0 (528.5–2592.0) |
1511.0 (800.5–4378.0) |
0.251 |
| Fibrinogen (mg/dL) a | 198.7 (125.4–418.8) | 151.9 (121.0–239.7) | 0.423 |
| Prothrombin time (INR) | 1.1 (0.96–1.3) | 1.2 (1.1–1.4) | 0.280 |
| aPTT (P/C ratio) | 1.1 (1.1–1.3) | 1.2 (1.1–1.4) | 0.704 |
Abbreviations: ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; CRP, C‐reactive protein; DH, disseminated histoplasmosis; GGT, gamma‐glutamyl transferase; HLH, haemophagocytic lymphohistiocytosis; HSJ, São José Hospital; INR, international normalised ratio; P/C, patient/control.
Available measurements: triglycerides (HLH 8/11; non‐HLH 13/50), fibrinogen (HLH 8/11; non‐HLH 9/50).
Regarding diagnostic methods, patients with H. capsulatum identified in peripheral blood had markedly higher odds of HLH (OR = 17.22; 95% CI: 2.75–141.95, p < 0.001). Positivity of diagnostic methods for DH is provided in Table 4.
TABLE 4.
Positivity of diagnostic methods of patients with HIV/AIDS and DH and association with HLH (n = 61), HSJ, Fortaleza, Brazil, 2023–2024.
| Diagnostic method | Non‐HLH (n = 50) | HLH (n = 11) | p |
|---|---|---|---|
| Urinary antigen | 29/32 (90.6%) | 8/8 (100.0%) | 1.000 |
| BC culture | 31/41 (75.6%) | 8/9 (88.9%) | 0.662 |
| Direct detection a in the BC | 25/43 (58.1%) | 7/9 (77.8%) | 0.454 |
| BMA culture | 4/7 (57.1%) | 2/3 (66.7%) | 1.000 |
| Blood culture | 7/16 (43.8%) | 2/3 (66.7%) | 0.582 |
| Direct detection a in the BMA | 3/8 (37.5%) | 1/4 (25.0%) | 1.000 |
| Direct detection a in the PB | 3/50 (6.0%) | 6/11 (54.5%) | < 0.001 |
| Direct detection a or culture on another site b | 3/50 (6.0%) | 1/11 (9.1%) | 0.559 |
Abbreviations: BC, buffy coat; BMA, bone marrow aspirate; DH, disseminated histoplasmosis; HLH, haemophagocytic lymphohistiocytosis; HSJ, São José Hospital; PB, peripheral blood.
Visualisation of H. capsulatum‐like yeasts.
Three patients had H. capsulatum‐like yeasts identified at other sites (two in bronchoalveolar lavage and one on a colon histopathological examination). Additionally, one patient had a positive culture from the pleural fluid.
Five bone marrow aspirates were performed in HLH patients, with haemophagocytosis detected in 60.0% (3/5). The two aspirates without evidence of haemophagocytosis were described as haemodiluted. Detailed HLH diagnostic criteria, clinical and epidemiological characteristics and treatment/outcomes are provided in Table 5.
TABLE 5.
Diagnostic criteria, H‐score, clinical, epidemiological, laboratory and therapeutic characteristics of patients with HIV/AIDS and DH who developed HLH (n = 11), HSJ, Fortaleza, Brazil, 2023–2024.
| Parameter | Pt 1 | Pt 2 | Pt 3 | Pt 4 | Pt 5 | Pt 6 | Pt 7 | Pt 8 | Pt 9 | Pt 10 | Pt 11 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Sex | M | F | M | M | M | M | M | M | F | M | M |
| Age (years) | 39 | 44 | 48 | 24 | 32 | 33 | 32 | 60 | 34 | 26 | 70 |
| CD4+ (cells/mm3) | 4 | 58 | 60 | 16 | 147 | 19 | 1 | 36 | 54 | 100 | 33 |
| HIV‐VL (log10 copies/mL) | 2.9 | 6.9 | 2.6 | 4.1 | 6.7 | 5.3 | NA | 6.3 | 2.3 | 3.1 | 6.0 |
| HLH‐2004 criteria (No.) | 4 | 5 | 4 | 4 | 5 | 5 | 3 | 4 | 4 | 5 | 4 |
| H‐score | 203 | 216 | 178 | 216 | 216 | 193 | 201 | 177 | 201 | 222 | 216 |
| Days of AmB a | 14 | 18 | 14 | 26 | 22 | 15 | 5 | 14 | 8 | 23 | 7 |
| Corticosteroid use | Yes | Yes | Yes | Yes | Yes | No | Yes | No | No | Yes | Yes |
| Outcome | Survived | Died | Survived | Died | Survived | Survived | Died | Survived | Survived | Died | Died |
| Days to outcome | 18 | 52 | 15 | 50 | 40 | 28 | 4 | 20 | 21 | 31 | 7 |
Abbreviations: AmB, amphotericin B; CD4, CD4+ T‐cell count; DH, disseminated histoplasmosis; F, female; HIV‐VL, HIV viral load; HLH, haemophagocytic lymphohistiocytosis; HSJ, São José Hospital; M, male; NA, not available; Pt, patient.
Days of amphotericin B therapy were calculated by combining deoxycholate, lipid complex and liposomal formulations.
The cumulative duration of AmB induction therapy did not differ between groups. HLH patients received a median of 14.0 days (11.0–20.0), whereas non‐HLH patients received 14 days (11.5–15.0) (p = 0.327).
Patients with HLH experienced a higher frequency of in‐hospital mortality. They required renal replacement therapy and ICU admission more frequently, with a non‐significant trend towards greater use of mechanical ventilation and vasoactive drugs (Table 6).
TABLE 6.
Outcomes of patients with HIV/AIDS and DH and association with HLH (n = 61), HSJ, Fortaleza, Brazil, 2023–2024.
| Outcome | Non‐HLH (n = 50) | HLH (n = 11) | OR | 95% CI | p |
|---|---|---|---|---|---|
| Vasoactive drug use | 12 (24.0%) | 6 (54.6%) | 3.70 | 0.79–18.46 | 0.067 |
| Mechanical ventilation | 11 (22.0%) | 6 (54.6%) | 4.13 | 0.87–20.85 | 0.058 |
| Renal replacement therapy | 10 (20.0%) | 6 (54.6%) | 4.67 | 0.97–23.80 | 0.028 |
| ICU admission | 19 (38.0%) | 8 (72.7%) | 4.24 | 0.88–27.88 | 0.048 |
| In‐hospital mortality | 9 (18.0%) | 6 (54.5%) | 5.27 | 1.08–27.50 | 0.019 |
Abbreviations: DH, disseminated histoplasmosis; HLH, haemophagocytic lymphohistiocytosis; HSJ, São José Hospital; ICU, intensive care unit.
Median time from hospital admission to death was 19.0 days (4.8–45.2) in the HLH group and 17.0 days (6.0–29.0) in the non‐HLH group. Kaplan–Meier survival analysis demonstrated significantly reduced in‐hospital survival among patients with HLH compared with those without HLH (log‐rank test, p = 0.015) (Figure 1).
FIGURE 1.
Kaplan–Meier estimates of in‐hospital survival according to haemophagocytic lymphohistiocytosis (HLH) status. Kaplan–Meier curves comparing in‐hospital survival between patients with and without HLH. Survival curves were compared using the log‐rank test (p = 0.015).
4. Discussion
HLH is a severe and potentially fatal hyperinflammatory syndrome characterised by excessive cytokine release, macrophage activation and immune dysregulation, often progressing to multiple organ failure [16]. Given its aggressive and rapidly fatal nature, early diagnosis and treatment are essential, as mortality approaches 100% in untreated patients [16, 17]. Although considered relatively rare [12, 18], HLH was identified in 18.0% of our study population, underscoring its clinical relevance. These findings highlight the need for systematic evaluation for HLH in PLWHA with DH, particularly those presenting with severe clinical forms.
The assessment of baseline severity using the HFS demonstrated that patients who developed HLH presented with a more severe clinical profile at hospital admission. Median HFS values were significantly higher in the HLH group, and all HLH cases were classified within the high‐risk category (HFS ≥ 5). These findings suggest that HLH tends to occur in patients with more advanced disseminated disease and heightened systemic inflammation at presentation.
The incomplete availability of diagnostic tests, particularly NK cell activity and soluble CD25, may have led to an underestimation of HLH prevalence. Moreover, some patients lacked essential investigations, including serum triglycerides, fibrinogen and ferritin. Bone marrow aspiration was infrequently performed, as less invasive tests were usually sufficient to diagnose DH. This limited the characterisation of HLH and reduced the proportion of patients who fulfilled at least five HLH‐2004 criteria. Reducing the threshold to three criteria, combined with H‐Score calculation, has been applied in similar studies [17] and was used here to increase diagnostic sensitivity. Although this approach may increase sensitivity, it may also reduce specificity.
HLH is strongly associated with HIV infection. An autopsy study of 54 patients with AIDS identified HLH in 20.4% of cases [19]. In French Guiana, DH accounted for 71.4% of HLH cases among PLWHA [18], highlighting the etiological spectrum of HLH in that setting. In the present study, the source population consisted exclusively of patients with AIDS‐related DH; therefore, HLH cases were observed within this clinical context. H. capsulatum is a leading opportunistic pathogen in advanced HIV infection in Ceará, Northeastern Brazil [4, 20, 21, 22, 23, 24]. Its immune evasion mechanisms, combined with host immunodeficiency, enable systemic dissemination and severe presentations [3]. Mortality rates for DH in PLWHA in Ceará range from 20.8% to 42% [20, 21, 24, 25]. Clinical features such as fever, splenomegaly, cytopenias, hypertriglyceridemia and hyperferritinemia—which overlap with HLH criteria—are frequent in AIDS patients regardless of opportunistic infections or ART, complicating differential diagnosis [10, 11].
Epstein–Barr virus (EBV) infection is the most common infectious trigger of HLH [26]. In the present study, EBV coinfection was observed exclusively in the non‐HLH group; however, only two patients were diagnosed with EBV infection. As EBV testing was not systematically performed, its contribution to HLH may have been underestimated. In PLWHA, the interplay between advanced immunosuppression, opportunistic infections such as DH, and viral triggers, including EBV, may create a permissive inflammatory environment for HLH development.
Haemoptysis, although reported in chronic pulmonary histoplasmosis [27], is uncommon in DH. It may occur in HLH due to massive immune activation, endothelial injury [12], coagulation abnormalities and platelet destruction [28]. In the present study, HLH patients more frequently exhibited haemoptysis and hepatomegaly. Haemoptysis has previously been reported in HLH associated with DH and leprosy [29]. Greater pulmonary involvement in HLH patients was also reflected by higher rates of mechanical ventilation (54.6% vs. 22.0%).
Hypertriglyceridemia and hypofibrinogenemia in HLH can be attributed to liver dysfunction and disseminated intravascular coagulation [30]. Macrophages are a significant source of ferritin, explaining the link between HLH and hyperferritinemia [31]. In our study, serum ferritin levels did not differ significantly between groups. However, 90.0% of HLH patients exceeded the laboratory's detection limit (> 1500 ng/mL), which limited further analysis.
Bone marrow haemophagocytosis is strongly associated with HLH diagnosis [32], but it is not pathognomonic. A study of 162 HLH patients reported a detection rate of 70.4% [33]. In our research, positivity was 60.0%, although BMA was performed in only 45.5% of HLH patients, with two aspirates being haemodiluted, reducing sensitivity.
The poor prognosis of HLH has been well documented. In PLWHA with DH and HLH, mortality has been reported at 37.1% [10], and approximately 41% in other studies [11, 12, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In French Guiana, mortality was lower (17.0%), attributed to awareness of local epidemiology, aggressive diagnostic and therapeutic approaches and early empirical antifungal therapy [18]. In Brazil, DH mortality in PLWHA remains high even without HLH, ranging from 22.1% to 42% [20, 21, 25, 46, 47]. Only one case of HLH associated with DH in a PLWHA has previously been reported in Brazil, diagnosed post‐mortem in a patient with advanced AIDS [48].
In our study, mortality was significantly higher in HLH patients (54.5% vs. 18.0%). Although the median time to death was similar between groups, the overall survival probability differed significantly. This may reflect the diagnostic complexity of HLH in the context of DH in PLWHA, potentially delaying diagnostic investigation and treatment initiation, and reinforces the clinical impact of HLH in this population.
The present study has several limitations. Owing to its retrospective design and the absence of precise timestamps for HLH diagnosis, it was not possible to determine whether HLH preceded clinical deterioration or emerged as a consequence of advanced disease, precluding causal inference regarding temporal relationships. Although the Histoplasma Fatality Score provided a standardised assessment of admission severity, it has not yet been formally validated in the Brazilian population. Furthermore, the lack of soluble CD25 measurement and NK‐cell activity assays prevented full application of the HLH‐2004 criteria, and incomplete testing in some patients may have limited HLH characterisation. Finally, as a single‐centre study with a relatively small sample size, statistical power may have been limited and some non‐significant findings may reflect insufficient power rather than the true absence of association. Given the number of comparisons, the possibility of a type I error cannot be excluded. Larger multicentre studies are warranted to confirm these findings.
5. Conclusion
To the best of our knowledge, this represents one of the largest contemporary studies examining HLH in association with DH among PLWHA, and it reports a high prevalence among adults diagnosed with DH. Multicentre studies with larger populations are needed to validate these findings and enhance their generalisability.
Investigations for HLH, including triglycerides, fibrinogen, ferritin and bone marrow aspirate evaluation for haemophagocytosis, are not consistently performed in routine DH management, particularly once fungal infection has been confirmed. However, such assessments may be critical, as a diagnosis based solely on classical criteria is often challenging. The H‐Score may provide useful additional support in suspected cases where HLH‐2004 criteria are incomplete. HLH may be more prevalent than previously recognised in PLWHA with DH. Given the substantial overlap in clinical and laboratory features, and the risk of adverse outcomes if diagnosis and treatment are delayed, HLH should be actively considered in patients with HIV/AIDS and DH who exhibit unfavourable clinical progression despite appropriate antifungal therapy.
Author Contributions
Jacó Ricarte Lima de Mesquita: investigation. Italo Oliveira Moura: investigation. Elizabeth De Francesco Daher: conceptualisation, investigation, writing – review and editing, project administration, methodology, supervision. Matheus Alves de Lima Mota: conceptualisation, investigation, writing – original draft, data curation, formal analysis, methodology, visualisation. Terezinha do Menino Jesus Silva Leitão: writing – review and editing. Gdayllon Cavalcante Meneses: data curation, formal analysis, methodology, validation, visualisation, writing – review and editing. Lisandra Serra Damasceno: writing – review and editing. Marcos Maciel Sousa: investigation. João Victor Monteiro Souza: investigation. Jéssica Maria de Sousa Oliveira: investigation.
Funding
This study was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. The funders had no role in the study design, data collection, data analysis, interpretation of results, manuscript preparation, or the decision to submit the manuscript for publication.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
The authors thank the physicians, residents, medical students, nurses and laboratory technicians at HSJ for their dedicated patient care and technical assistance throughout the study. The authors also acknowledge Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil, for institutional support.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request. The availability of these data is restricted due to privacy and ethical considerations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request. The availability of these data is restricted due to privacy and ethical considerations.