ABSTRACT.
Typhoid fever can have diverse extra-intestinal complications including encephalitis, Guillain-Barré syndrome, endocarditis, myocarditis, osteomyelitis, renal abscess, and splenic abscesses. Secondary hemophagocytic lymphohistiocytosis with rhabdomyolysis is a rare complication of typhoid fever. Here, we present the case of an adolescent with typhoid fever complicated by rhabdomyolysis and hemophagocytic lymphohistiocytosis.
CASE REPORT
A 17-year-old boy was admitted with an intermittent fever up to 38.9°C for 2 days approximately 7 days before admission, followed by severe myalgia for 5 days and decreased urine output for 2 days. On admission, he was febrile 37.8°C, with tachycardia (heart rate of 106/minute), blood pressure of 124/76 mm Hg, respiratory rate of 20 per minute, and an SpO2 of 96% on room air. He was drowsy but arousable with absent meningeal signs, motor power of 4+/5 in all four limbs, and preserved deep tendon reflexes. Laboratory investigation revealed anemia of 13.1 g/dL (reference range [RR]: 13–16 g/dL), thrombocytopenia of 18 × 109/L (RR: 150–450 × 109/L), leucopenia of 1.4 × 109/L (RR: 4–11 × 109/L), blood urea of 96 mg/dL (RR: 10–50 mg/dL), creatinine of 2.01 mg/dL (RR: 0.5–1.2 mg/dL), aspartate transaminase of 970 U/L (RR: 2–40 U/L), and alanine transaminase of 150 U/L (RR: 2–41 U/L) (Table 1). Ultrasonography of the abdomen showed a mildly enlarged liver and spleen, mild ascites, and a few enlarged centimetric periportal lymph nodes. Tropical infection was suspected, and the patient was started on injections of ceftriaxone 1 g intravenous (IV) twice a day and doxycycline 100 mg IV twice a day. Tests for dengue NS-1 antigen, malaria antigen, dengue IgM, scrub IgM, and Leptospira IgM were negative. His typhoid serologies for IgM and IgG were positive, and his Widal titers were TH 1:160 (increased to 1:320 in a day); T0 1:320; AH < 1:20; and BH < 1:20, even though his blood cultures were sterile. He also had an elevated creatinine phosphokinase (CPK) value of 24,339 U/L (RR: 26–308 U/L), serum myoglobin of 961 ng/mL (RR: 28–72 ng/mL), and urine myoglobin of 2,634 ng/mL (RR: nil in urine), suggestive of rhabdomyolysis. A hemophagocytic lymphohistiocytosis (HLH) workup showed an elevated ferritin value of 11,707 ng/mL (RR: 30–400 ng/mL), low fibrinogen value of 1.89 g/L (RR: 2–4.8 g/L), elevated triglyceride value of 570 mg/dL (RR: 50–200 mg/dL), cytopenias, and elevated liver enzymes, and a bone marrow examination showed marked hemophagocytosis (Figure 1A–D) (seven of eight HLH-2004 criteria). A diagnosis of complicated typhoid fever with rhabdomyolysis and secondary HLH was made, and IV immunoglobulin (IVIG) was added with a total dose of 1.6 g/kg over 3 days. After IVIG therapy, he showed improvement in both clinical and laboratory parameters (Table 1).
Table 1.
Trends of laboratory parameters during hospital stay and after discharge
| Parameter | At admission (day 0) | At third day of IVIG (day 5) | At discharge (day 7) | At follow-up (day 12) | Reference range |
|---|---|---|---|---|---|
| Hemoglobin (g/dL) | 13.1 | 11.2 | 11 | 11.6 | 13–16 |
| Total leukocyte count (× 109/L) | 1.4 | 7.0 | 13.11 | 13.51 | 4–11 |
| Platelet count (× 109/L) | 18 | 80 | 127 | 210 | 150–450 |
| Blood urea (mg/dL) | 96 | 38.2 | 23.5 | 25.4 | 10–50 |
| Creatinine (mg/dL) | 2.01 | 0.75 | 0.67 | 0.62 | 0.5–1.2 |
| Aspartate transaminase (U/L) | 970 | 584 | 290 | 88.1 | 2–40 |
| Alanine transaminase (U/L) | 150 | 176 | 142 | 100.5 | 2–41 |
| Creatinine phosphokinase (U/L) | 24,339 | 1,369 | 546 | 357 | 26–308 |
| Ferritin (ng/mL) | 11,707 | 2,432 | 1,097 | – | 30–400 |
| Triglycerides (mg/dL) | 570 | 255 | – | – | 50–200 |
| C-reactive protein (mg/L) | 210 | 36.74 | – | – | 0–5 |
| Fibrinogen assay (g/L) | 1.89 | 1.35 | 1.33 | – | 2–4.8 |
| D-dimer assay (ng/mL) | 25,000 | 6,135 | 2,309 | – | 0–240 |
| Urine myoglobin (ng/mL) | 2,634 | – | 660 | – | Nil |
| Serum myoglobin (ng/mL) | 961 | – | 193 | – | 28–72 |
IVIG = intravenous immunoglobulin.
Figure 1.
Micro photographs of bone marrow aspirate. (A) Scanner view of bone marrow aspirate showing cellular particles (May Grünwald–Giemsa stain, magnification ×40). (B) Bone marrow aspirate smear showing the presence of many histiocytes with evidence of hemophagocytosis (arrows) along with the presence of normal hematopoietic elements (magnification ×200). (C) A histiocyte showing the presence of nucleated cells in its cytoplasm (arrow) (magnification ×400). (D) Another histiocyte showing the presence of platelets in the cytoplasm (arrow) (magnification ×400).
DISCUSSION
The severity of typhoid fever depends on the infective dose and virulence of the organism. The usual incubation period is 1 to 14 days. Fever is the most common presenting symptom, others being abdominal pain, headache, constipation, diarrhea, weakness, dizziness, nausea, vomiting, and cough. Complications such as intestinal perforation, gastrointestinal hemorrhage, hepatitis, pancreatitis, cholecystitis, myocarditis, shock, encephalopathy, hemolytic uremic syndrome, pneumonia, and disseminated intravascular coagulation usually start in the second week of illness. Hemophagocytic lymphohistiocytosis and rhabdomyolysis secondary to typhoid fever are uncommon.1–4
Hemophagocytic lymphohistiocytosis results from immunological hyperactivation of macrophages and T-cells resulting from defective cytotoxicity, leading to the release of various proinflammatory cytokines and multiorgan failure along with phagocytosis of host cells by the activated macrophages. In patients with infection-associated HLH, treating the triggering cause will be enough to withdraw the immune activation and control the inflammatory cytokine storm. However, in cases of no response, immunomodulator therapy with steroids, IVIG, etc., may be required, as in our index case.3–5
The cause of acute kidney injury in enteric fever is multifactorial, with rhabdomyolysis being one of the causes even though the exact mechanism of the development of rhabdomyolysis in enteric fever is not precisely known. Some proposed mechanisms are tissue hypoxia due to sepsis, direct bacterial invasion, activation of lysosomal enzymes, endotoxin release, and altered muscle metabolic capacity caused by low oxidative and glycolytic enzyme activities. Rhabdomyolysis presents with a triad of myalgia, weakness, and dark-colored urine. Diagnosis is made through clinical and laboratory findings such as the elevation of CPK, serum, and urine myoglobin levels. A literature review of 19 case reports of enteric fever–associated rhabdomyolysis showed varying levels of CPK from 1,124 to 64,000 U/L (median: 6,341 U/L); our index case had a value of 24,339 U/L at the time of presentation. Management includes mainly the prevention of acute kidney injury with aggressive hydration.6–8
ACKNOWLEDGMENT
The American Society of Tropical Medicine and Hygiene (ASTMH) assisted with publication expenses.
REFERENCES
- 1. Mukhopadhyay B, Sur D, Gupta SS, Ganguly NK, 2019. Typhoid fever: control & challenges in India. Indian J Med Res 150: 437. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Marchello CS, Birkhold M, Crump JA, 2020. Complications and mortality of typhoid fever: a global systematic review and meta-analysis. J Infect 81: 902–910. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Yasar AS, Karaman K, Geylan H, Çetin M, Güven B, Öner AF, 2019. Typhoid fever accompanied with hematopoetic lymphohistiocytosis and rhabdomyolysis in a refugee child. J Pediatr Hematol Oncol 41: e233–e234. [DOI] [PubMed] [Google Scholar]
- 4. Non LR, Patel R, Esmaeeli A, Despotovic V, 2015. Case report: typhoid fever complicated by hemophagocytic lymphohistiocytosis and rhabdomyolysis. Am J Trop Med Hyg 93: 1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Madkaikar M, Shabrish S, Desai M, 2016. Current updates on classification, diagnosis and treatment of hemophagocytic lymphohistiocytosis (HLH). Indian J Pediatr 83: 434–443. [DOI] [PubMed] [Google Scholar]
- 6. Uribe-Londono J, Castano-Jaramillo LM, Penagos-Tascon L, Restrepo-Gouzy A, Escobar-Gonzalez AF, 2018. Hemophagocytic lymphohistiocytosis associated with Salmonella typhi infection in a child: a case report with review of literature. Case Rep Pediatr 2018: 6236270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Ata F, Marzouk SK, Bilal AB, Khan AA, Ibrahim E, Almadani MT, 2021. Drug-resistant Salmonella typhi induced kidney injury with rhabdomyolysis: a case report, and literature review. IDCases 24: e01103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Torres PA, Helmstetter JA, Kaye AM, Kaye AD, 2015. Rhabdomyolysis: pathogenesis, diagnosis, and treatment. Ochsner J 15: 58–69. [PMC free article] [PubMed] [Google Scholar]