Editor's Note: Invasive fungal infection (IFI) refers to a fungal infection that invades the deep tissues and organs of the human body, causing pathological changes such as tissue damage, organ dysfunction, and inflammatory responses. IFI is a serious complication among patients with severe liver disease, with a poor prognosis and high mortality rate. The clinical presentation is often atypical, and antifungal medications, which are mostly metabolized in the liver, have significant toxic side effects, making diagnosis and treatment challenging. At the 10th "Silk Road Hepatology" Academic Conference, Dr. Jia Shang from the Infectious Disease Department at Henan Provincial People’s Hospital shared a clinical case of a severe liver disease patient who developed IFI. The details of this case are summarized below for our readers.Case Information
The patient is a 61-year-old female who, five years ago, presented with “jaundice” at a local hospital, where she was diagnosed with cirrhosis. She subsequently came to our hospital for a liver biopsy to clarify the etiology and was diagnosed with autoimmune hepatitis. She received prednisone, azathioprine, ursodeoxycholic acid, and Diyu Shengbai tablets, with a reduced maintenance dose of steroids. However, in August 2023, she discontinued her medication on her own. The patient has a history of diabetes for over nine months, intermittently treated with insulin, with unstable blood glucose levels and no current hypoglycemic medication. Two months prior, she developed abdominal distension without an apparent cause, accompanied by poor appetite, fatigue, and yellowing of the skin and sclera. She was treated at a local clinic for “gastroenteritis” with traditional Chinese medicine (details unknown) but saw little improvement. Her abdominal distension worsened, and she developed fever, poor appetite, and edema in both lower limbs. After testing positive for Mycoplasma antibodies at a local clinic, she was treated with an unknown medication, leading to a temporary reduction in fever. However, her temperature fluctuated, reaching a maximum of 38.7°C, accompanied by cough and phlegm. Since the onset of illness, her weight had increased by 30 pounds.
Initial Hospital Admission and Treatment
On January 1, 2024, the patient was admitted for examination. She was conscious but in poor spirits, of normal development, with a “liver face” appearance. She had a regular heart rhythm, with no murmurs in the valve auscultation areas, coarse breath sounds in both lungs, no crackles, a distended abdomen without varicosities, soft to touch, no tenderness or rebound pain, positive shifting dullness, and normal bowel sounds (3 times per minute), with edema in both lower limbs.
Laboratory results:
- Complete blood count: WBC 0.93×10^9/L, neutrophils 0.44×10^9/L, RBC 3.7×10^12/L, hemoglobin 119 g/L, platelets 41×10^9/L.
- Coagulation function: PT 14.4 s, PTA 71%, D-dimer 4.3 μg/mL.
- Blood biochemistry: ALT 38.7 U/L, AST 43.3 U/L, total protein 47.47 g/L, albumin 10.53 g/L, total bilirubin 31.04 μmol/L, direct bilirubin 15.24 μmol/L, ALP 160 U/L, GGT 166.4 U/L, creatinine 165 μmol/L, glucose 2.00 mmol/L.
- Immunology: ANA (IF) 1:1000 nucleolar type, LC1 positive, AMA type 2 positive, Ro52 positive, anti-U1-nRNP antibody (WB) positive, ANCA negative.
- Other markers: Immunoglobulin G 23.78 g/L, CRP 86.93 mg/L, PCT 7.04 ng/mL.
Other tests showed negative blood culture, positive influenza A nucleic acid, and negative viral hepatitis (HAV, HBV, HCV, HEV), ceruloplasmin, and normal thyroid function.
CT scan revealed inflammation in both lungs, local consolidation, and multiple enlarged mediastinal and bilateral axillary lymph nodes.
Initial diagnosis: Autoimmune liver disease overlap syndrome (relapse after drug withdrawal), decompensated cirrhosis post-hepatitis, pulmonary infection, influenza A, type 2 diabetes with hypoglycemia, possible ascites with multi-organ dysfunction.
Treatment plan:
- Liver support and enzyme reduction: Magnesium isoglycyrrhizinate, glutathione, ademetionine, UDCA.
- Diuresis: Albumin supplementation, furosemide, spironolactone, tolvaptan.
- Antibiotics: Biapenem 300 mg (dose adjusted for renal insufficiency), peramivir 0.3 g.
- Primary disease treatment: Methylprednisolone 40 mg (January 4), gradually tapered until January 24.
- Other supportive therapies: Thrombopoietin, granulocyte colony-stimulating factor, glucose supplementation with blood glucose monitoring.
On January 4, a paracentesis was performed, showing a WBC count of 246×10^6/L, polymorphonuclear count of 120×10^6/L. Following antifungal and steroid treatment, blood glucose rose on January 5, and insulin was added. Gradual renal function recovery followed the use of antibiotics, albumin, and paracentesis. Terlipressin was started on January 5, and creatinine decreased to 90.9 μmol/L by January 13.
January 10 review: Serum G-test <10.00, serum GM test 0.282; PCT 1.09 ng/mL, CRP 49.39 mg/L; WBC 1.09×10^9/L, neutrophils 0.44×10^9/L, RBC 2.51×10^12/L, hemoglobin 78.0 g/L, platelets 48×10^9/L; ALT 14.6 U/L, AST 12.3 U/L, albumin 21.49 g/L, total bilirubin 33.12 μmol/L, ALP 128.4 U/L, GGT 125.5 U/L, creatinine 114.7 μmol/L; PT activity 46.5%.
Smear of sputum showed fungal spores, with multiple pathogens detected by sputum tNGS testing. The patient declined further bronchoscopy. According to the “Expert Consensus on Diagnosis and Treatment of Invasive Fungal Infection in Severe Liver Disease,” a diagnosis of liver disease with fungal infection was made. Voriconazole was started at 150 mg every 12 hours on January 12, with plasma drug concentration monitoring. Fever, which had been recurring, subsided by January 13. CT on January 17 showed significant improvement.
Discharge and follow-up: The patient was discharged on January 24 with methylprednisolone, mycophenolate mofetil, ursodeoxycholic acid, and ademetionine for liver disease, with oral voriconazole to continue antifungal treatment, and insulin for blood glucose control. On February 5, lab tests showed stable condition, with improved CT results indicating steady recovery.
Second Hospital Admission and Treatment
On February 19, 2024, the patient was readmitted due to a rapid deterioration of her condition, marked by fever (up to 38.5°C), increased cough, chest tightness, shortness of breath, and fatigue. Initial assessment showed oxygen saturation at 83%, heart rate 128 bpm, BP 78/42 mmHg, and temperature 38.7°C, suggestive of septic shock, leading to ICU admission.
Lab results:
- Complete blood count: WBC 1.62×10^9/L, neutrophils 1.06×10^9/L, RBC 2.53×10^12/L, hemoglobin 87 g/L, platelets 122×10^9/L.
- Coagulation: PT 14.2 s, PTA 77.7%.
- Blood biochemistry: ALT 219.8 U/L, AST 121.5 U/L, total protein 55.21 g/L, albumin 23.7 g/L, total bilirubin 12.1 μmol/L, direct bilirubin 9.09 μmol/L, ALP 263.9 U/L, GGT 125.1 U/L, creatinine 196.6 μmol/L.
- Other markers: NT-proBNP 1120 pg/mL.
Influenza A, B, respiratory syncytial virus, and SARS-CoV-2 nucleic acid tests were negative, as was Mycoplasma. Voriconazole plasma concentration was >16 μg/mL with instability. CRP 134.62 mg/L, PCT 2.12 ng/mL, serum G-test <10.00 pg/mL, serum GM test 0.383.
CT scan indicated worsening of her condition, and combined clinical, radiological, and microbiological evaluations confirmed disease progression.
Treatment adjustment: Literature suggests posaconazole, which bypasses the CYP450 metabolic pathway, as having lower direct bilirubin levels and lower hepatotoxicity than voriconazole. Thus, posaconazole is recommended for chronic pulmonary aspergillosis (CPA) by European Society of Clinical Microbiology and Infectious Diseases (ESCMID)/ERS guidelines and as salvage therapy for CPA by IDSA guidelines.
After stopping voriconazole, meropenem was administered, and posaconazole 300 mg/day was initiated on February 23. CT on February 28 showed improvement. Maintenance treatment continued with posaconazole, mycophenolate mofetil, and methylprednisolone, along with insulin for glucose control and albumin for diuresis. On March 4, liver and kidney function tests showed gradual improvement.
By May 2, 2024, follow-up tests showed continued recovery in liver and kidney function, with stable counts of WBC, platelets, and PCT.
Insights and Experience
The exact cause of autoimmune hepatitis is unclear, likely involving genetic susceptibility and environmental factors, leading to a loss of tolerance to liver antigens. Drug withdrawal has a high risk of recurrence, possibly causing immune cell damage, leading to fluid accumulation and lung obstruction, potentially resulting in death.
Glucocorticoids are commonly used immunosuppressants that inhibit macrophage phagocytosis and antigen processing, quickly reducing immune and inflammatory responses, preventing liver failure progression. Timely glucocorticoid use is critical to address cytokine storms in autoimmune hepatitis recurrence.
Immunocompromised patients are at high risk for fungal infections with poor prognosis. Early diagnosis, pathogen identification, targeted treatment, and strict infection control measures are essential, alongside personalized adjustments to treatment.
Increasing rates of IFI in severe liver disease patients underscore the need for vigilant assessment of fungal infection risks in immunocompromised patients with fever or pneumonia to improve prognosis and reduce complications.
Timely and accurate antifungal drug choice is crucial, favoring liver-safe options. Voriconazole can cause hepatic dysfunction and, rarely, liver failure. Regular blood concentration monitoring is essential to avoid adverse effects. Among triazoles, posaconazole has minimal hepatotoxicity and may reduce invasive pulmonary aspergillosis in liver failure patients on glucocorticoids, potentially improving survival with fewer adverse effects. Posaconazole remains an effective salvage therapy if itraconazole or voriconazole fail, alleviating drug-related liver damage and promoting gradual recovery.
