When the usual is unusual – An uncommon presentation of enteric fever

INTRODUCTION

Enteric fever, caused by Salmonella enterica serovar Typhi and, less commonly, Paratyphi A, B or C, is an acute infectious disease transmitted through the faecal-oral route, primarily through contaminated food or water. It remains a major health issue in regions like India, with an estimated 4.5 million cases annually and a low case fatality rate of 0.2%. Common symptoms include high fever, abdominal pain, headache, gastrointestinal disturbances (constipation or diarrhoea) and general malaise.^[1] Without timely antibiotic treatment, serious complications can arise, such as intestinal perforation, gastrointestinal bleeding, hepatitis, cholecystitis, myocarditis, shock, encephalopathy, pneumonia and anaemia. The disease can range from mild febrile illness to life-threatening sepsis and multi-organ failure. Diagnosis is confirmed by blood cultures, and treatment involves antibiotics such as fluoroquinolones, third-generation cephalosporins or azithromycin. Preventive measures include improved sanitation, vaccination and safe food and water practices. We report a case of a previously healthy female with a history of travel from Bali with typhoid fever complicated by sepsis, conductive hearing loss and a rare complication, hemophagocytic lymphohistiocytosis (HLH).

CASE REPORT

This case involves a 24-year-old female with a history of hypothyroidism, with recent travel history to Bali, who presented with high-grade fever of 12-day duration associated with headache, myalgia, dizziness and loose stools with occasional blood in stools, along with abdominal pain and multiple oral ulcers. Her fever persisted despite initial treatment with antibiotics (augmentin and ceftriaxone). She also developed acute-onset bilateral conductive hearing loss. On examination, she was febrile had pallor, and multiple oral ulcers, but no signs of jaundice, cyanosis or oedema with a heart rate of 145 bpm, blood pressure 110/70 mmHg and oxygen saturation of 99%. There were no significant findings on cardiovascular or respiratory examination, and abdominal examination was soft and non-tender. Investigations revealed a falling haemoglobin (from 11.1 g/ dL to 6.0 g/dL), declining platelet count and total count and elevated liver enzymes, with high procalcitonin levels (11.78), suggesting an infectious cause. Stool and blood cultures as well as tests for common tropical infections such as dengue, typhoid, malaria, rickettsial fever, scrub typhus, brucella and leptospirosis and immunoglobulin-M, hepatitis A virus, hepatitis E virus, cytomegalovirus, herpes simplex virus were negative. However, imaging (contrast-enhanced computed tomography abdomen) showed mild hepatosplenomegaly, mucosal thickening in the terminal ileum and mesenteric lymphadenopathy, which raised concern for an infective or inflammatory aetiology.

Further workup included a colonoscopy, which revealed active ileocolitis with ulcers in the terminal ileum, caecum and ascending colon, suggestive of an infective origin, likely salmonella. Keeping a possibility of HLH, serum ferritin and triglycerides were sent. Her serum ferritin was significantly elevated and her triglyceride was elevated with low fibrinogen. She had fever, hepatosplenomegaly, pancytopenia, elevated ferritin and elevated triglycerides which satisfied HLH 2004 criteria. Bone marrow aspiration with biopsy showed hypocellular marrow with erythrophagocytic histiocytes (hemophagocytosis) confirming HLH along with hyperferretinemia, hypofibrinogenaemia and hypertriglyceridaemia with cytopenias and hepatosplenomegaly [Figure 1 and Figure 2a-b]. Bone marrow culture was positive for multidrug-resistant Salmonella Typhi, confirming the diagnosis. The patient was started on IV azithromycin and amikacin, and given the possible HLH, corticosteroid therapy (dexamethasone) was initiated. Her clinical condition improved rapidly, with resolution of fever, normalisation of blood counts and improvement in hearing.

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Figure 1:

Bone marrow biopsy showing hemophagocytosis of lymphocyte (yellow arrow). Stain: Romanowsky stain, Magnification: 200x.

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Figure 2:

(a and b) Bone marrow biopsy showing hemophagocytosis of lymphocyte and neutrophil (yellow arrows). Stain: Romanowsky stain, Magnification: 200x.

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Histopathological examination of the colon biopsies confirmed active ileocolitis with features suggestive of Salmonella infection. The patient was transfused with two units of packed red blood cells to manage her anaemia. Over the course of treatment, her inflammatory markers improved, and she became afebrile and haemodynamically stable. She was discharged with follow-up instructions for continued monitoring of blood counts, liver function and further surveillance for potential complications, including hearing recovery and monitoring for HLH.

This case underscores the importance of a thorough diagnostic approach in the evaluation of fever of unknown origin with pancytopenia and multisystem involvement, leading to the identification of Salmonella-induced ileocolitis and HLH, which required prompt antibiotic and corticosteroid treatment for recovery. This case also emphasises the difficulty in diagnosing a fever of unknown origin already treated with multiple antibiotics, where cultures will come negative and the final diagnosis was made from bone marrow culture and also the uncommon presentation of a very common disease.

DISCUSSION

Typhoid fever, caused by Salmonella enterica serotype Typhi and, less commonly, S. Paratyphi A, B and C, is a systemic infectious disease transmitted primarily through the ingestion of contaminated food or water. The clinical spectrum of typhoid fever ranges from mild febrile illness to severe toxemia with multi-organ involvement. Approximately 10–15% of patients may develop severe disease, often complicated by gastrointestinal bleeding, intestinal perforation or typhoid encephalopathy.

Typhoid encephalopathy, manifesting as confusion, insomnia and dizziness, occurs in 3–10% of cases and is associated with increased mortality. Other rare but reported complications include hepatic and splenic granulomas, liver abscesses, pleural effusion, multiple organ dysfunction syndrome, hemophagocytic syndrome (HPS), haemolytic uraemic syndrome, glomerulonephritis and pericarditis. Early recognition of such complications is critical, as timely and appropriate interventions can significantly reduce morbidity and mortality.^[2]

CONCLUSION

The occurrence of HPS (HLH) in patients with complicated typhoid fever is a rare but critical consideration. Given the potential for rapid deterioration, timely recognition and the initiation of appropriate treatment, including immunosuppressive therapy, are vital. Clinicians should maintain a high index of suspicion for HLH in patients with complicated infections and cytopenias, and a multidisciplinary approach is essential for optimising outcomes in these critically ill patients.