Severe Aplastic Anemia Complicated with Fatal Invasive Fungal Infections in a Young Patient Harboring Perforin Gene Polymorphisms

Abstract

Background: Severe aplastic anemia (SAA) is an uncommon life-threatening disorder characterized by hypocellular bone marrow and pancytopenia. It is typically associated with immune-mediated mechanisms, requiring immunosuppressive therapy (IST) or hematopoietic stem cell transplantation (HSCT). Infections, especially invasive fungal infections such as mucormycosis and aspergillosis, constitute principal causes of morbidity and mortality in patients with SAA. Genetic predispositions, including perforin (PRF1) polymorphisms, may further complicate disease outcomes by impairing immune function.

Case report: We describe a case of a 36-year-old female patient diagnosed with SAA, for whom IST was considered, due to the unavailability of a matched sibling donor for HSCT. The patient presented with a feverish condition and deep neck space abscesses were revealed by imaging, caused by invasive aspergillosis. To prioritize infection control, IST was postponed and antifungal therapy with abscess drainage was initiated. However, aspergillosis progressed, despite aggressive and prompt treatment, and ultimately resulted in sepsis, multiorgan failure, and death. In addition, mucormycosis was confirmed post-mortem. Two heterozygous PRF1 polymorphisms (c.272C>T and c.900C>T), were identified by genetic testing, which may have contributed to immune dysregulation and fungal dissemination.

Conclusions: The complex interplay between managing SAA and addressing invasive fungal infections, which remain a leading cause of mortality in immunocompromised patients, is highlighted in this case. The latter emphasizes the importance of prompt diagnosis and targeted treatment to alleviate infection-related complications while maintaining care continuity for the hematologic disorder. The detection of PRF1 polymorphisms raises questions about their implication in immune regulation and disease trajectory, emphasizing the need for further research in this field.

Keywords: aspergillosis; immunosuppressive therapy; mucormycosis; perforin gene mutation; severe aplastic anemia.

Figure 1

Bone marrow biopsy. (A). Markedly hypocellular bone marrow with stromal edema (hematoxylin-eosin stain; ×400). (B). The predominant cell population corresponds to T cells (CD3, ×400), with rare cytotoxic cells (inset: Granzyme B, ×400). (C). The arrows depict macrophages with foamy cytoplasm.

Figure 2

Timeline of key clinical events and hematologic parameters.

Figure 3

Neck and chest CT scan. (A,B). An axial and mid-sagittal image showing a large fluid collection of low attenuation with surrounding rim-enhancement (arrow) and some gaseous foci in the posterior aspect of the nasopharynx (arrow), measuring 3.3 × 4.1 × 2.8 cm, consistent with abscess formation. (C,D). An axial mid-sagittal image depicting another abscess in the retropharyngeal space (arrow) extending from the level of C2 vertebral body, to the C6 level with a craniocaudal diameter of 6.3 cm and a maximum depth of 1 cm, with a significant fat stranding extending into the visceral and carotid spaces, bilaterally. (E,F). Axial images depicting a small consolidation in the apicoposterior segment of the left upper lobe (arrow) and a lobar consolidation with ground-glass opacification in the right middle lobe (arrow). (G). Axial image showing centrilobular nodules with a linear branching pattern (tree-in-bud) in the lower lobes and in the lingula (arrow). (H,I) Axial images showing nodules up to 5 mm, some of them with a ground-glass halo, in the lower lobes (arrow), predominantly peripheral in distribution.

Figure 4

Aspergillus spp. Histopathology. Hyphae with acute branching angle (<45°) or dichotomous branching septate hyphae (blue arrows) and fragments of hyphae (red arrow) (hematoxylin-eosin stain; ×400).