Extended drug-resistant Salmonella Typhi complicated by rare fatal haemophagocytic lymphohistocytosis: A case report

Case report

A 23-year old married female, with no prior comorbidity, presented as an emergency with vaginal bleeding for 15 days together with fever and loose stools for 10 days. On examination, she was pale and dehydrated, normotensive at 100/70 mmHg, tachycardic at 120/min, febrile at 38.3°C with a respiratory rate of 18/min maintaining saturation on room air. A pelvic ultrasound scan showed a missed abortion (Table 1) for which an evacuation was performed.

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Table 1.

Patient investigations during hospital course.

Investigations	1st Day	3rd Day	5th Day	7th Day	10th Day
Hb (g/L)	71	86	82	75	87
Total leukocyte count (x 109/L)	5.4	2.8	2.5	3	3.7
Neutrophils	76%	35.4%	39.2%	41%	53%
Lymphocytes	18.8%	63%	54.8%	49.3%	34%
Platelet counts (x 105/L)	166	139	85	74	117
Creatinine	45.09 µmol/L
Bilirubin total	11.45 µmol/L
Bilirubin direct	6.32 µmol/L
Gamma glutamyl transferase (GGT)	590 U/L
Alanine aminotransferase (SGPT/ALT)	52 U/L
Alkaline phosphatase (ALP)	470 U/L
Ferritin			2.238 g/ml
Triglycerides			4.48 mmol/l
Fibrinogen			3.6 g/L

On the second day of admission, she had documented high-grade fever of 38.9°C for which cultures were sent. Her condition had not significantly changed; an impression of typhoid fever was made and Meropenem injections commenced.

The abdominal ultrasound scan showed moderate hepatosplenomegaly but the repeat pelvic scan reported no retained product of conception. On the 4th day of admission, the blood culture duly reported Salmonella enterica serovar Typhi; Meropenem injections were thus continued. However, she continued spiking high-grade fever with worsening cytopenia. She developed an epistaxis and became hypotensive, prompting High Dependency Unit care.

Considering the worsening clinical condition and cytopenia, an haemophagocytic lymphohistiocytosis (HLH) workup was requested, which was positive with a H-score of 205 points: fever of 38.9°C (49 pts), 3 cell lineages involved (34 pts), splenomegaly (23 pts), ferritin >2000μg/L (35 pts), triglyceride levels >3 mmol/L (64 ps) with remaining criteria including AST, bone marrow, fibrinogen having 0 pts) representing a 88–93% probability of HLH.

She was immediately started on Dexamethasone injections according to her body surface area together with the Meropenem injections. Within 48 h, her fever subsided, and her cytopenias improved. By the 10th day of admission, she became afebrile for >48 h and was discharged on oral azithromycin and tapering doses of dexamethasone. After 1 week, she could be discharged and stayed afebrile with normal cell counts.

Discussion

HLH is a clinical syndrome of an uncontrolled hyper-inflammatory state, classified into primary and secondary HLH. While primary HLH is due to genetic defects in the immune system, secondary HLH can be triggered by infections, malignancy and autoimmune diseases. The incidence of primary HLH is approximately 1.2 per million individuals but the exact incidence of secondary HLH is not known and can be critical in 22–59% of patients. ¹ Very few cases of Salmonella enterica serovar Typhi causing HLH have been reported with none due to extended drug resistant (XDR) Salmonella enterica serovar Typhi to date. ²

HLH can be a challenging diagnosis as it mimics many diseases of similar clinical and laboratory manifestation with multi-organ involvement. It is confirmed by the HLH 2004 diagnostic criteria consisting of molecular diagnosis or fulfilment of five out of eight following criteria: fever, splenomegaly, cytopenia, hypertriglyceridaemia and/or hypofibrinogenaemia, haemophagocytosis in bone marrow, spleen or lymph nodes, low or absent NK cell activity, hyperferritinaemia and soluble CD25 > 2400 U/ml.

While severe onset secondary HLH cases require early and aggressive immunosuppressive therapy (steroids v. intravenous immunoglobulins), HLH cases caused by bacterial and parasitic infections usually benefit from targeted anti-infectious treatment alone. The addition of immunosuppressants in Salmonella enterica serovar Typhi-related HLH cases may be dependent on organ failure and the clinical condition of patients.^3,4 In a detailed literature review, only two out of 11 patients required immunosuppression with antibiotics for recovery. ⁵ Our patient had persistent fever and worsening cytopenias that improved only after addition of high-dose dexamethasone probably as XDR Salmonella enterica serovar Typhi can be quite aggressive compared to other Salmonella strains. Owing to the rarity of this association, there are no randomized controlled trials for testing potential therapy. However, supportive care and treatment of the inciting infectious trigger are associated with a 60–70% chance of recovery. ³

Management for HLH needs to be started quickly so that irreversible organ damage can be halted. The overall prognosis of secondary HLH depends on the aetiology with patients having malignancy reporting the worst prognosis. ² Salmonella enterica serovar Typhi-related HLH usually has a good prognosis overall.