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.