INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) describes a cytokine storm that is due to uncontrolled accumulation of activated T-lymphocytes and activated histiocytes. This results in organ infiltration with these cells, and subsequent hemophagocytosis of erythrocytes, leukocytes and platelets. In its most severe form, HLH leads to a sepsis-like picture and multiorgan failure (MOF). We report the case of an adult male that presented with severe adenovirus pneumonia (AVP) resulting in HLH with acute respiratory distress syndrome (ARDS) and MOF. This association may at least in part explain the recently observed increase in the incidence of fatal adenoviral infections.
CASE PRESENTATION: A 22-year old male with a remote history of juvenile rheumatoid arthritis (JRA) was admitted with a 3-day history of dyspnea, productive cough and fever that did not respond to outpatient treatment with a macrolide. The patient had not been on immunosuppressive medications for >2 years. Chest CT on admission revealed diffuse dense bilateral infiltrates (Fig. 1). Despite treatment with broad spectrum antibiotics, the patient remained febrile and developed rapidly pogressive hypoxic respiratory failure requiring mechanical ventilation. Bronchoalveolar lavage (BAL) initially did not reveal any pathogens. The patient developed shock, acute renal failure and metabolic acidosis, requiring multiple pressors and renal replacement therapy. Stress-dose hydrocortisone was added without improvement. Four days after bronchoscopy, the BAL viral culture grew adenovirus. The patient continued to exhibit severe hypoxia as well as hypercarbia and died of respiratory failure on hospital day 12. During the patient's clinical deterioration, ferritin increased from 757 to 9490 ng/ml, and platelets decreased from 180.000 to 36.000/mm3. Disseminated intravascular coagulation was excluded. The patient also developed hypertriglyceridemia (499 mg/dl) and anemia (8.6 mg/dl). The bone marrow biopsy did not show any evidence of hemophagocytosis. However, the postmortem examination revealed macrophages with hemophagocytosis and lymphophagocytosis in a hilar lymph node (Fig. 2). Decreased natural killer (NK) cell activity was detected in the patient's blood, although this result was not available until after the patient's demise. Based on these results, a postmortem diagnosis of adenovirus-induced HLH was made.
DISCUSSIONS: In immunocompetent patients, adenovirus infection usually causes self-limited upper respiratory tract infections. While cases of severe AVP in immunocompetent adults have been described, the overall incidence is extremely rare. Recently, several cases of fatal AVP in previously healthy patients were reported. Some of these were linked to adenovirus serotype 14. HLH, while being associated with viral pathogens such as herpes simplex or Ebstein-Barr virus, malignancies, autoimmune diseases, drugs, genetic and familial conditions, has also been associated with adenoviral infections. The diagnosis of HLH is based on a combination of clinical and laboratory criteria. These include fever, splenomegaly, cytopenia of ≥2 cell lines, hyperferritinemia, hypertriglyceridemia, increased soluble interleukin-2 receptor levels, decreased or absent NK-cell activity and hemophagocytosis in bone marrow, cerebrospinal fluid or lymph nodes. The syndrome is often misdiagnosed as sepsis, thereby precluding the potentially curative treatment with corticosteroids, immunosuppressants and/or chemotherapeutic agents. It is conceivable that the recently observed increase in virulence of adenoviral infections may at least in part be due to an association with HLH. The patient's history of JRA may have made him particularly susceptible.
CONCLUSION: HLH is a syndrome of life-threatening hyperinflammation that may be misdiagnosed as sepsis. The association of HLH with severe AVP observed in our patient suggests a potential mechanism for the recently reported increase in the incidence of extremely virulent adenoviral infections.
DISCLOSURE: Tim Lahm, No Financial Disclosure Information; No Product/Research Disclosure Information