Discussion
This was a remarkable case of cavitary pneumonia caused byKlebsiella pneumoniae in the setting of recurrent pneumonias by the same organism complicated by HLH. Klebsiella pneumonia is known to be a serious infection and prompts a grim prognosis. Once the organism enters human body, it is notorious to display high degree of virulence and antibiotic resistance3. It is considered one of the most common cause of hospital acquired pneumonia in the United States. Host factors that predispose to colonization and infection include intensive care unit admission, immunocompromised individuals, prolonged use of invasive devices, and broad spectrum antibiotics. Prognosis is worst in diabetics, alcoholics, elderly, and immunocompromised. Even with ideal therapy, it carries a mortality risk of 30-50%4,5.
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life threatening condition characterized by overstimulation of the immune system which leads to systemic inflammation, hypercytokinemia and multi-organ failure2. It can be either primary or secondary. Primary HLH typically presents in childhood, and is mainly caused by genetic mutations in cytotoxic activity of natural killer (NK) cells and T-cells. Secondary HLH is mainly triggered by immunologically activating processes such as infection, neoplasm, or autoimmune processes. Viral infections, such as Epstein-Barr virus, cytomegalovirus, herpes virus, and human immunodeficiency virus are known to be associated with secondary HLH. Bacterial infections causing HLH are less common, with the majority related to Mycobacterium tuberculosis 6. To the best of our knowledge, association of HLH and Klebsiella pneumoniae is rarely reported in the literature.
Hemophagocytosis is an increasingly accepted endpoint of immune dysregulation in sepsis. Evaluation of HLH in septic patients with pancytopenia is not routine, but should be in differential as delay in diagnosis can be detrimental. The diagnosis is established based on criteria in HLH-2004 trial7 . Moreover, there could be subsequent delay associated with procuring NK cell activity, soluble IL-2 receptor levels, and bone marrow biopsy thus necessitating concurrent empiric therapy in few cases8. In our case, diagnosis for HLH was achieved as he met 5 out of the 8 criteria which included fever, cytopenia, elevated ferritin levels, triglyceridemia, and hemophagocytosis on bone marrow biopsy9. NK cell activity and sIL2r are important objective markers, even if not tested, diagnosis can be guided by other parameters which are readily available.
HLH secondary to infection is mostly treated with dexamethasone as per the HLH-2004 study as the severity of the disease process warrants an immunosuppressive therapy. Dexamethasone being the preferred steroid because of its highest CNS penetration. In a systematic review by Hayden et al., treatment was highly variable both between and within the studies. Amongst them, sixteen of the eighteen study groups followed etoposide-based treatment, which was also offered to our patient10. It has been shown that early initiation of etoposide, within four weeks of symptoms in pediatric population have higher survival benefit compared to individuals receiving etoposide after 4 weeks11,12. Also, in a retrospective study conducted by Arca and colleagues in 162 adults with HLH, a trend towards better outcomes was observed when etoposide was employed (85% vs. 74% survival, p=0.079)13. Our patient’s immunosuppressive therapy could have contributed to development of recurrent Klebsiella pneumonia infection, but he did not develop HLH again.
As this is a condition observed more widely in pediatric population, it is imperative that new biomarkers and therapies conducted in children should also be promptly studied in adult population14. For example, interferon gamma has shown to be a key mediator in HLH, and a pediatric anti-interferon gamma antibody is currently under phase-1 clinical trial15. Another pediatric study is underway using hybrid immunotherapy called the HLH-HIT trial (anti-thymocyte immunoglobulin, dexamethasone, and etoposide). These trials can help inform future studies in adult HLH15.