Two-Hot-to-Handle

Dr Porpon Rotjanapan Attending Physician, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

A 36-year-old Thai male, previously in good state of health, was admitted in a local hospital for diagnosis of dengue infection, based on a positive IgM serology. He initially presented with low-grade fever and malaise for 2 days. Three days later, he developed respiratory distress requiring intubation and he was subsequently transferred to Ramathibodi Hospital. Initial work up revealed massive left hemothorax, for which chest tube drainage was done. Dengue PCR was positive for dengue virus type 2 with a viral load of 7,000,000 copies/mL, 7 times higher than the level seen among the average infected population.

On the first hospital day, hemophagocytic syndrome was diagnosed, given the evidence of bicytopenia (anemia and thrombocytopenia), elevated ferritin >10,000 ng/mL and confirmatory bone marrow study findings. He received intravenous immunoglobulin but no corticosteroids or other immunosuppressive drugs.

On the fourth hospital day, screening for serum galactomannan by ELISA was positive (2.67; reference range 0-0.49 Ag Index). Micafungin was started as prophylaxis.

On the eighth day of the illness, a small faint round nodule was observed over the right upper lung field on chest radiograph and a repeat galactomannan test showed 2.50. A diagnosis of probable IPA was made. Antifungal therapy was switched from micafungin to amphotericin B deoxycholate. However, the pulmonary lesion continued to grow larger over time. Chest CT exhibited multiple pulmonary nodules with the largest measuring 3 cm in diameter, located in the right upper lobe. Bronchoscopy was performed and BAL galactomannan was 4.63 (reference range 0-0.49 Ag Index). Eighteen days later, BAL culture reported Aspergillus terreus with a minimum inhibitory concentration (MIC) of 0.075 to posaconazole. At this point, antifungal therapy was switched to voriconazole temporarily, and then to intravenous posaconazole once available, because of hepatotoxicity concern. Aside from a prolonged course of antifungal treatment, patient had likewise been adequately covered with courses of antibiotics for bacterial pneumonia and bacteremia.

Throughout the hospital course, the patient had persistent lymphopenia with peak CD4 count of 8 cells/mL (1%). His condition continued to deteriorate until he required left pneumonectomy for infection control. Apart from intravenous posaconazole, micafungin and flucytosine were added, aiming for synergistic effect. Despite therapeutic posaconazole levels in the plasma, pleural fluid and lung tissue, serum galactomannan continued to rise and peaked at 8.97 prior to his death.

Key learning points

In addition to prolonged neutropenia, treatment with chemotherapy and corticosteroid use, severe dengue infection has been reported to be an associated cause of invasive aspergillosis in some case series.¹ The potential explanation is the strong inhibition of nuclear factor-kB that is important for lymphocyte and neutrophil proliferation,² causing eventual reversal in the CD4/CD8 ratio.³ Th2- type response with elevated IL-10 and IL-4 levels in severe dengue infection might enhance susceptibility to invasive aspergillosis as well.^4,5 With these possibilities, severe dengue infection can potentially create an immunocompromised status in a previously healthy individual, predisposing the patient to opportunistic infections.^1,3 This is consistent with a case series study from our hospital that described four patients who initially had severe dengue infection but later succumbed due to severe invasive aspergillosis within 14 days of onset of dengue infection.¹

References:

1. Larbcharoensub N, et al. Southeast Asian J Trop Med Public Health 2011;42:1106-1112.
2. Wati S, et al. J Gen Virol 2011;92:807-818.
3. Liu CC, et al. J Med Virol 2002;68:241-252.
4. Chaturvedi UC, et al. Curr Sci 1999;76:63-69.
5. Schmid MA, et al. Front Immunol 2014;5:647.