ACRT Journal

Abdominal Organs:

Esophagus: Mucosa showing autolysis, but otherwise within normal limits.

Stomach: Mucosa showing autolysis and mild vascular congestion, but otherwise within normal limits.

Pancreas: Autolytic changes present.

Kidneys: H&E, PAS, and JSS stains of the left and right kidneys show renal parenchyma with no evidence of diabetic changes, scarring, or nephrosclerosis.

Liver: Significant autolytic changes. Mild cholestasis. Mild macrovesicular steatosis and mild portal lymphocytic infiltration. No significant iron deposition. No alpha-1-antitrypsin inclusions. No cirrhosis, or malignancy seen. Special stains of Trichrome, iron, PAS and Reticulin support the findings.

Gallbladder: Autolytic changes, otherwise within normal limits. No calculi identified.

Spleen: Tissue architecture and cellular morphology showing many hemophagocytic cells highlighted with CD68 and CD163.

Lymph Nodes: Paracortical expansion with numerous histiocytes actively phagocytosing hematopoietic elements. Hemophagocytic cells highlighted with CD68 and CD163.

Bone Marrow: Hypercellular marrow (70% cellularity) with trilineage hematopoiesis. Many hemophagocytic cells are identified. Trabecular bone is unremarkable. CD68 and CD163 highlights hemophagocytic activity. CD61 highlights megakaryocytes. Iron: minimal iron storage; could be suboptimal due to decalcification of bone.

Final Autopsy Diagnosis:

I. Hemophagocytic lymphohistiocytosis (HLH) (meets 6/8 criteria)

a. Clinical findings of:

i. Fever ii. Hypofibrinogenemia (117 mg/dL; 12/1/2024) iii. Hyperferritinemia (>40000 ng/mL;12/1/2024) iv. Cytopenias (Hgb 8.7 g/dL and Platelets 21 K/cumm; 12/1/2024)

v. Elevated IL2 receptor (CD25) (47375 pg/mL)

b. Histologic findings:

1. Evidence of hemophagocytosis in the bone marrow, spleen and lymph node
2. Clusters of intravascular histiocytes in the pulmonary system identified

II. Clinical findings of septic shock (per chart patient meets 3/4

SIRS criteria)

1. Sputum culture: Positive for Escherichia coli and Candida albicans (11/30/2024)

b. R. typhi IgM and IgG detected (titers >= 1:256); confirmed with realtime PCR (California Department of Public Health)

1. Elevated Mycoplasma IgG titers (0.94 - equivocal)

III. Cardiovascular system

1. Heart weight: 410 grams
2. Focal calcification in the aortic valve
3. Atherosclerotic calcification identified in left anterior descending artery (60%), left circumflex artery (30%) and right coronary artery (70%)
4. Moderate patchy atherosclerosis of the descending and abdominal aorta with severe calcification (plaque-forming), no evident dissection

IV. Respiratory system (Right lung 1000 Grams; Left lung 1010

Grams)

1. Pulmonary congestion bilaterally with pulmonary edema and interstitial inflammation and fibrosis
2. Clusters of intravascular histiocytes

V.  Liver

1. Hepatomegaly (Wt: 2240 grams)
2. Mild macrosteatosis
3. Cholestasis

Discussion

Hemophagocytic lymphohistiocytosis (HLH) is a rare but highly lethal hyperinflammatory syndrome characterized by aberrant activation of cytotoxic T-cells and macrophages, leading to excessive cytokine release and multi-organ destruction [1,3,5]. HLH can present as either a primary (genetic) or secondary (acquired) disorder [1,3,5]. In adults, secondary HLH is often associated with infections (notably EBV), malignancies (especially T-cell or NKcell lymphomas), and autoimmune conditions [3,4,6].

This case highlights the diagnostic challenges associated with HLH, particularly in adult patients, where clinical signs often overlap with sepsis or malignancy-related cytokine storms [3,4,6]. Despite fulfilling several HLH-2004 criteria, including hyperferritinemia, cytopenias, and evidence of hemophagocytosis on bone marrow and splenic histology, the diagnosis was not made until post-mortem [1,2]. Autopsy findings included splenomegaly with extensive hemophagocytosis, hepatic sinusoidal histiocytosis, and reactive lymphadenopathy, consistent with advanced HLH (9,10). These findings emphasize the systemic nature of the disease and the role of autopsy in confirming a diagnosis when ante-mortem suspicion is low [10,11]. (Table 2).

Table 2: HS Score for decedent. Categories in bold is the decedent’s score.

Histologically, the presence of activated histiocytes engulfing erythroid, myeloid, and platelet precursors across multiple organs serves as a diagnostic hallmark [1,5]. However, hemophagocytosis is neither sensitive nor specific in early disease and may be absent in initial biopsies [1,3]. The delay in clinical recognition and lack of immediate initiation of HLH-directed therapy (e.g., dexamethasone, etoposide) and the original HLH trigger likely contributed to the fulminant disease course in this patient [1,3,4].

Clinically, the patient presented with nonspecific but severe systemic manifestations, including persistent fever, cytopenias, hepatosplenomegaly, and progressive multiorgan dysfunction [3,4,6]. These features are consistent with the clinical phenotype of hemophagocytic lymphohistiocytosis, yet they overlapped with more common differential diagnoses such as sepsis, disseminated malignancy, or autoimmune flares [3,4]. Laboratory evaluation revealed markedly elevated ferritin and liver function abnormalities, both of which are frequently reported in HLH and correlate with the cytokine-driven hyperinflammatory state [3,4,5]. Rickettsia typhus was suspected and sent for out testing during the clinical course on 11/21/24. Despite these red flags, the diagnosis was not established during life, underscoring the diagnostic difficulty of HLH in adults and the need for quicker turnaround times for send out laboratory testing [3,4,6]. In this case, postmortem identification of Salmonella Typhi strongly suggests that typhoid fever may have served as the inciting event for secondary HLH. Although viral agents remain the most frequent triggers of HLH, S. Typhi an intracellular pathogen has been implicated in both adult and pediatric HLH cases. For instance, one report describes a 24-year-old man with fever, altered mental status, rash, gastrointestinal bleeding, and confirmed hemophagocytosis on bone marrow examination in the context of complicated typhoid fever [3]. Another describes a 21-year-old woman who developed HLH and rhabdomyolysis during typhoid fever [6]. Even pediatric cases such as a four-year-old with fever, diarrhea, pancytopenia, and HLH diagnosed via bone marrow biopsy support this association [7]. A literature review including patients from non-endemic regions also documented consistent clinical features including prolonged fever and cytopenias demonstrating that this is a global, albeit rare, phenomenon [8]. The pathophysiology likely involves persistent intracellular infection with S. Typhi, leading to dysregulated activation of macrophages and T-lymphocytes, culminating in the cytokine storm and hemophagocytosis. This suggests that early recognition of HLH in typhoid patients especially those with unremitting fever, cytopenias, and multiorgan dysfunction could be life-saving when combined with targeted immunomodulatory therapies.

Conclusion

This case reinforces the importance of a multidisciplinary approach and the utility of applying HLH scoring systems (such as HScore) in patients with unexplained systemic inflammatory response, especially in those with risk factors like recent infections, malignancy, or autoimmune disease. Autopsy played a pivotal role in confirming the diagnosis, providing closure for the clinical team, and contributing to quality improvement by identifying a missed diagnosis. HLH should be considered in any patient with unexplained multiorgan dysfunction, cytopenias, and elevated inflammatory markers, especially when initial infectious workups are negative. Early identification and prompt treatment are paramount, and this case serves as a powerful reminder of the diagnostic value of autopsy in modern medicine.

Acknowledgments

We would like to thank the staff, faculty, resident physicians and the decedent’s family that helped contributed to this publication and learning opportunity.

Conflict of Interest Statement

This autopsy was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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