Authors: Laurentia Ima Monica, Bagus Setyoboedi, Dwiyanti Puspitasari, Dominicus Husada, Parwati Setiono Basuki, Ismoedijanto Ismoedijanto
Categories: Case Report, case report, cholestatic hepatitis, electrolyte imbalance, pancytopenia, pleural effusion, typhoid fever
Source: International Journal of Surgery Case Reports
Authors: Laurentia Ima Monica, Bagus Setyoboedi, Dwiyanti Puspitasari, Dominicus Husada, Parwati Setiono Basuki, Ismoedijanto Ismoedijanto
Typhoid fever remains a significant public health concern in endemic regions, with a broad clinical spectrum. Although multisystem manifestations such as pancytopenia, electrolyte imbalance, cholestatic hepatitis, and pleural effusion have been reported individually, the coexistence of all four complications in a single patient is exceedingly uncommon and poses substantial diagnostic challenges.
We report the case of a 15-year-old female adolescent with typhoid fever presenting with atypical features, including progressive pancytopenia, severe hyponatremia with hypokalemia, cholestatic hepatitis, and right-sided pleural effusion. Despite the initial diagnosis suggesting dengue fever, blood culture confirmed Salmonella enterica serovar Typhi. She was managed with intravenous antibiotics, fluid and electrolyte correction, and adjuvant corticosteroid therapy for cholestatic hepatic dysfunction. Clinical and laboratory improvement was achieved without invasive interventions.
The pathophysi.ological mechanisms underlying these complications are multifactorial, involving bone marrow suppression, peripheral destruction, and hypersplenism in pancytopenia; persistent gastrointestinal losses or syndrome of inappropriate antidiuretic hormone secretion in electrolyte imbalance; hepatocellular dysfunction, immune-mediated cholestasis, and canalicular transport disruption in cholestatic hepatitis; and increased pleural capillary permeability triggered by endotoxin and systemic inflammation in pleural effusion. This uncommon constellation may mimic other systemic bacterial infections, such as tuberculosis, in an endemic region like Indonesia, potentially leading to unnecessary invasive procedures.
Early recognition of atypical typhoid fever with uncommon multisystem complications is crucial. Conservative management with targeted antimicrobial therapy, fluid and electrolyte correction, and adjuvant corticosteroids when indicated remains the cornerstone for achieving optimal outcomes.
Typhoid fever remains a major public health concern in endemic countries, particularly across Asia^[^1^]^. Recent epidemiological data indicate that the prevalence of typhoid fever remains high in South Asia, especially in India, Pakistan, and Bangladesh, with an incidence exceeding 150 cases per 100 000 population per year, whereas East Asian countries such as Japan, Korea, and Taiwan report substantially lower rates^[^2^]^. Although complications such as pancytopenia, electrolyte imbalance, cholestatic hepatitis, and pleural effusion have been individually described in typhoid fever, the coexistence of all four manifestations in a single patient is exceedingly uncommon and poses significant diagnostic challenges^[^3–6^]^. We report the case of a female adolescent with typhoid fever presenting with atypical manifestations, including pancytopenia, electrolyte imbalance, cholestatic hepatitis, and pleural effusion. This case report has been prepared in accordance with the updated Surgical Case Report 2025 guidelines^[^7^]^.
A 15-year-old female adolescent presented with a 5-day history of intermittent fever, which temporarily subsided with paracetamol. She reported dizziness, nausea, and recurrent vomiting after meals, with more than four episodes, the last occurring prior to admission. She also experienced watery diarrhea for 3 days, with more than five times daily, without mucus or blood. No rash, bleeding gums, or other hemorrhagic signs were observed. There was no history of chronic illness, malignancy, or autoimmune disease in the patient or her family.
On physical examination, the patient appeared pale with asymmetric lower-limb edema, while vital signs and capillary refill remained normal. Initial laboratory evaluation revealed cytopenia with mild normocytic normochromic anemia, accompanied by severe hyponatremia and hypokalemia. Inflammatory markers were elevated, whereas renal function was within normal limits. Dengue serology was negative, and chest radiography demonstrated clear lung fields without pleural effusion (Fig. 1). Figure 1.Chest radiograph on day 5 of illness shows clear lung fields and normal cardiac silhouette without evidence of pleural effusion or consolidation.
The initial diagnosis was dengue fever with warning signs. The patient received intravenous fluid and oral paracetamol. On day 8, worsening cytopenia and persistent hyponatremia prompted revision of the diagnosis after Tubex® Salmonella IgM returned positive. Intravenous ampicillin–sulbactam was initiated, and blood culture subsequently confirmed Salmonella enterica serovar Typhi, sensitive to multiple antibiotics. Stool culture was not performed as diarrhea had improved, and no additional gastrointestinal complaints were noted.
Despite targeted therapy, progressive pancytopenia and persistent electrolyte imbalance, necessitating escalation to intravenous ceftriaxone. On day 12, hemoglobin levels declined further, and chest radiography revealed right-sided pleural effusion (Fig. 2). Figure 2.Chest radiograph on day 12 of illness showing increased opacity in the right lower lung field with elevation and obscuration of the right hemidiaphragm, consistent with right-sided pleural effusion and mediastinal shift to the left.
On day 15, the patient developed jaundice. Liver function test demonstrated elevated transaminases, hypoalbuminemia, and hyperbilirubinemia, with additional abnormalities in gamma-glutamyl transferase (GGT), alkaline phosphatase (AP), international normalized ratio (INR), and partial thromboplastin time (PTT). Abdominal ultrasonography revealed mild hepatomegaly with diffuse increased echogenicity, consistent with cholestatic hepatitis, without focal lesions or biliary obstruction. Given the severity of hepatic dysfunction and systemic inflammation, empirical corticosteroid therapy with oral prednisone (2 mg/kg/day) was initiated. Autoimmune markers were negative, and hepatic injury was attributed to atypical systemic manifestation of typhoid fever.
By day 16, hematologic improvement was evident with rising platelet counts, and chest radiography showed resolution of the pleural effusion (Fig. 3). Immunological and viral tests, including ANA, anti-dsDNA, HBsAg, anti-HCV, and dengue serology, were all negative. Complement levels were within normal limits. Due to persistent fever and gastrointestinal symptoms, ciprofloxacin was added to the antibiotic regimen. Supportive therapies included zinc supplementation and probiotics. Figure 3.Chest radiograph on day 16 of illness showing partial resolution of the right-sided pleural effusion, with improved lung aeration and normalization of the right hemidiaphragm contour.
On day 26, the patient showed marked clinical afebrile, anicteric, and free of gastrointestinal symptoms. Peripheral edema had resolved, and oral prednisone was tapered gradually. A detailed chronology of the clinical course, laboratory dynamics, and therapeutic decisions is presented in Table 1. The patient remained under outpatient follow-up with scheduled visits at 2 weeks, 1, 3, and 6 months post-hospitalization. At the latest follow-up, no relapse or significant adverse effects were observed, and sustained recovery was documented.Table 1Chronological summary of clinical course.Day of illnessClinical findingsLaboratory (normal parameter)/ imagingManagementDay 5 (admission)High-grade fever, recurrent vomiting, watery diarrhea, generalized weakness, asymmetric lower-limb edema.Hb 11.8 g/dL (≥12 g/dL), WBC 2500/µL (3500–9000/µL), Plt 75 000/µL (157 000–371 000/µL); K 2.3 mmol/L (3.5–5.2 mmol/L), Na 128 mmol/L (135–145 mmol/L); CRP 65 mg/L (0.3–1 mg/dL), PCT 2.1 ng/mL (<0.1 ng/dL); SC 0.8 mg/dL (0.59–1.04 mg/dL), BUN 21 mg/dL (6–21 mg/dL); Dengue IgM/IgG negative; Chest X-ray: normalIntravenous fluids (Ringer’s lactate), oral paracetamol, electrolyte correction, supportive care, and close monitoring.Day 8Persistent fever, ongoing diarrhea, hyponatremia, hypokalemia, worsening cytopenia.Hb 10.2 (≥12 g/dL), WBC 2270/µL (3500–9000/µL), Plt 37 000/µL (157 000–371 000/µL); K 3.2 (3.5–5.2 mmol/L), Na 131 mmol/L (135–145 mmol/L); Tubex Salmonella IgM positive.Diagnosis revised to typhoid fever; intravenous ampicillin-sulbactam initiated.Day 9Persistent fever, diarrhea improved, cytopenia.Blood Salmonella enterica serovar Typhi (sensitive to ampicillin, cefotaxime, ceftriaxone, ciprofloxacin, chloramphenicol)Therapy guided by the blood culture result.Day 12Progressive pancytopenia, persistent electrolyte imbalance, chest discomfort, right-sided pleural effusion.Hb 8.3 g/dL (≥12 g/dL), erythrocyte 3.4 million/µL (4.2–5.4 million/µL), WBC 2460/µL (3500–9000/µL), Plt 36 000/µL (157 000–371 000/µL), Hct 27.2% (36%–46%); K 2.5 mmol/L (3.5–5.2 mmol/L), Na 132 mmol/L (135–145 mmol/L); Chest X-ray: right-sided pleural effusion.Antibiotic regimen escalated to intravenous ceftriaxone.Day 15Jaundice, peripheral edema, persistent diarrhea.AST 412 U/L (10–40 U/L), ALT 218 U/L (7–56 U/L), hypoalbuminemia 2.83 g/dL (3.5–5 g/dL), total bilirubin 2.27 mg/dL (0.3–1.2 mg/dL), direct bilirubin 1.35 mg/dL (0.1–0.3 mg/dL), GGT 165 U/L (5–36 U/L), AP 312 U/L (30–100 U/L), INR 1.42 (0.8–1.2), PTT 41 s (11–13.5 s); liver mild hepatomegaly.Oral prednisone 2 mg/kg/day initiated as adjunctive therapy.Day 16Clinical improvementHb 10.6 g/dL (≥12 g/dL), WBC 2980/µL (3500–9000/µL), Plt 123 000/µL (157 000–371 000/µL); Na 138 mmol/L, K 4.4 mmol/L; ANA 14.6 (<40: negative), anti-dsDNA 1.12 (<30: negative); C3 116 mg/dL (82–185 mg/dL), C4 38.1 mg/dL (15–53 mg/dL); viral hepatitis C markers negative; Chest X-ray: resolution of pleural effusionContinued ceftriaxone, added ciprofloxacin, zinc, and probiotics.Day 19 (discharge)Afebrile, diarrhea improved, mild jaundice, residual edema.Hb 10.6 g/dL (≥12 g/dL), WBC 2680/µL (3500–9000/µL), Plt 123 000/µL (157 000–371 000/µL), Hct 32.4% (36%–46%); K 4.4 mmol/L (3.5–5.2 mmol/L), Na 138 mmol/L (135–145 mmol/L).Discharged on tapering oral prednisone.Day 26 (follow-up)Fully recovered (afebrile, anicteric, no edema, no diarrhea).-Outpatient follow-up, steroids tapered.2 weeks post-dischargeClinically stable.Hb 12.2 g/dL (≥12 g/dL), WBC 4100/µL (3500–9000/µL), Plt 182 000/µL (157 000–371 000/µL), HCT 37.4% (36%–46%), K 3.6 mmol (3.5–5.2 mmol/L), Na 140 mmol/L (135–145 mmol/L).Steroids discontinued.1, 3, and 6 months post-dischargeClinically stable.Hb 12.4 g/dL (≥12 g/dL), WBC 5700/µL (3500–9000/µL), Plt 218 000/µL (157 000–371 000/µL), HCT 37.2% (36%–46%), K 3.9 mmol (3.5–5.2 mmol/L), Na 138 mmol/L (135–145 mmol/L)Routine follow-up; no relapse observed.ALT, alanine aminotransferase; ANA, antinuclear antibody; Anti‑dsDNA, anti‑double stranded DNA antibody; AP, alkaline phosphatase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; C3, complement 3; C4, complement 4; CRP, C‑reactive protein; GGT, gamma‑glutamyl transferase; Hb, hemoglobin; Hct, hematocrit; INR, International normalized ratio; K, kalium; Na, natrium; PCT, procalcitonin; Plt, platelet count; PTT, partial thromboplastin time; SC, serum creatinine; WBC, white blood cell count.
Typhoid fever remains a major public health concern in endemic regions of Asia^[^1^]^, including Indonesia^[^8^]^, may present atypically with multisystem involvement such as pancytopenia^[^4^]^, electrolyte imbalance^[^3^]^, cholestatic hepatitis^[^5^]^, and pleural effusion^[^6^]^. The combination of these manifestations occurring simultaneously in an adolescent is uncommon^[^3–6^]^, although pathophysiologically possible in the context of severe systemic infection, as demonstrated in this case^[^9^]^.
Pathophysiologically, pancytopenia in typhoid fever may occur through several mechanisms. First, bone marrow suppression due to immune activation and release of proinflammatory cytokines may trigger hemophagocytosis, resulting in reduced production of erythrocytes, leukocytes, and platelets. This mechanism has been reported in typhoid patients with prominent hemophagocytosis on bone marrow biopsy^[^4^]^. Second, peripheral destruction or consumption of blood cells may also contribute, for example through immunological processes, disseminated intravascular coagulation, or reactive hemophagocytosis in tissues. This is supported by case reports of typhoid-associated pancytopenia with active marrow without hypocellularity, in which hematologic parameters improved once infection was controlled^[^4,10^]^. Third, hypersplenism due to splenomegaly, frequently accompanying severe typhoid, may lead to sequestration of erythrocytes, leukocytes, and platelets, thereby exacerbating cytopenia^[^4,11^]^. Thus, the mechanisms of pancytopenia in typhoid are multifactorial, involving marrow suppression, peripheral destruction or consumption, and splenic sequestration^[^4,10,11^]^.
Electrolyte disturbances in this case, namely hyponatremia and hypokalemia, can be explained by two principal mechanisms. First, persistent gastrointestinal losses due to prolonged diarrhea or vomiting result in sodium and potassium depletion, usually accompanied by clinical signs of dehydration and low urinary sodium; hypokalemia accompanying hyponatremia is characteristic of this mechanism^[^12^]^. Second, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur as a response to systemic infection, in which excessive ADH release causes free water retention without sodium retention, leading to dilutional hyponatremia. Patients with SIADH typically appear euvolemic, with high urinary sodium and persistently elevated urinary osmolality despite low serum sodium; this condition is uncommonly associated with hypokalemia and does not improve with fluid administration alone, requiring fluid restriction or specific therapy^[^13^]^. Therefore, hyponatremia in typhoid may result from gastrointestinal loss or SIADH, and identifying the underlying mechanism is crucial, as management fluid and electrolyte replacement for gastrointestinal loss, versus fluid restriction for SIADH^[^12–14^]^.
In this case, cholestatic hepatitis can be explained by complex pathophysiological mechanisms. First, direct effects of Salmonella enterica endotoxin may induce hepatocellular dysfunction and cholestasis through membrane injury and activation of inflammatory mediators. Second, immune-mediated cholestasis occurs due to T-cell activation and release of proinflammatory cytokines such as TNF-α and IL-6, which disrupt hepatobiliary homeostasis. Third, canalicular transport dysfunction contributes through altered expression and function of transporter proteins, including bile salt export pump (ABCB11) and multidrug resistance protein 2 (MRP2), thereby impairing bile flow. These multifactorial mechanisms explain why the patient’s biochemical profile resembled biliary obstruction but improved with antibiotic therapy^[^15,16^]^.
From a surgical perspective, pleural effusion in this case represented a challenging complication, as it may mimic tuberculosis or bacterial pneumonia, both common in endemic regions such as Indonesia^[^17,18^]^. To exclude other causes, blood culture successfully identified Salmonella enterica serovar Typhi as the gold standard, supported by Tubex® Salmonella IgM immunoassay. Although initial IgG and IgM results were negative, this is consistent with the limited diagnostic accuracy of early ELISA testing, which often yields false negatives^[^19,20^]^. Pathophysiologically, typhoid-related pleural effusion is generally reactive, triggered by increased pleural capillary permeability due to Salmonella enterica endotoxins and systemic inflammatory response, rather than primary suppurative processes. This mechanism explains why most typhoid-associated pleural effusions resolve with appropriate antibiotic therapy without invasive intervention, as demonstrated in this case where effusion improved following targeted treatment^[^6,21^]^.
This condition underscores the importance for clinicians in endemic areas to consider atypical typhoid before deciding on invasive interventions, as multisystem complications may mislead diagnosis and influence clinical decision-making. With appropriate management, patients can be spared from high-risk procedures that provide no therapeutic benefit^[^2,4,22^]^. In this case, the decision to avoid invasive intervention was based on hemodynamic stability, absence of active bleeding, and preserved hepatic function within compensatory limits. Thresholds that typically prompt intervention include clinical indications (massive gastrointestinal bleeding, intestinal perforation, severe encephalopathy, or refractory shock) and biochemical criteria (INR >2.0 unresponsive to supportive therapy or platelet count <20 000/µL with active bleeding)^[^23^]^. Intervention for pleural effusion is considered only in the presence of significant respiratory symptoms (severe dyspnea, hypoxemia, or fluid volume >1500 mL), evidence of infection (empyema, pH <7.2), or suspicion of malignancy, in accordance with the British Thoracic Society Guideline^[^24^]^.
Initial therapy did not yield improvement and was followed by worsening electrolyte imbalance (persistent hyponatremia and hypokalemia), progressive pancytopenia, and the emergence of cholestatic hepatitis and pleural effusion. Corticosteroids were subsequently administered because the patient exhibited signs of cholestatic hepatic dysfunction with significant systemic inflammation. Literature reports that corticosteroids may be used as adjunctive therapy in severe typhoid hepatitis and immunological complications, with a role in modulating excessive inflammatory responses, thereby accelerating hepatic recovery and preventing progression of organ injury. Administration was performed cautiously with close monitoring of hepatic function, hematology, and clinical status, consistent with management guidelines for severe typhoid complications, which emphasize that adjunctive therapy should only be considered in cases with significant systemic inflammation and risk of organ failure^[^23,25,26^]^.
One limitation of this case report is the absence of immunological titers. This reflects the diagnostic limitations in typhoid-endemic regions with restricted resources such as Indonesia, where blood culture remains the gold standard, while immunological assays serve only as supplementary tests.
This case underscores that typhoid fever can give rise to uncommon multisystem complications occurring simultaneously, including pancytopenia, severe electrolyte imbalance, cholestatic hepatitis, and pleural effusion. The underlying pathophysiological mechanisms are multifactorial, encompassing bone marrow suppression, peripheral destruction, and hypersplenism in pancytopenia; gastrointestinal loss and SIADH in electrolyte imbalance; hepatocellular dysfunction, immune-mediated cholestasis, and canalicular transport impairment in cholestatic hepatitis; as well as increased pleural capillary permeability due to endotoxin and systemic inflammation in pleural effusion. Such complexity may mimic other common diseases in endemic regions, thereby posing a risk of unnecessary invasive interventions. Clinical improvement following targeted antimicrobial therapy, fluid and electrolyte correction, and adjunctive corticosteroid administration demonstrates that a conservative approach with vigilant diagnostic evaluation remains the cornerstone strategy. This report highlights the importance of early recognition of atypical typhoid manifestations to prevent misdiagnosis and to ensure optimal clinical outcomes.