Hemophagocytic Lymphohistocytosis (HLH)

I did not really come across any tropical illness that was truly really any interest to me. I did come across two patients that had the above disease so I decided to write my one and a half page blurb on it: HLH is also known as the autosomal recessive familial hemophagocytic lymphohistiocytosis (FHL), familial erythrophagocytic lymphohistiocytosis (FEL), and viral-associated hemophagocytic syndrome (VAHS). Twenty-five percent of all HL H cases are familial and are frequently associated with parental consanguinity. It is a life-threatening disease most often affects infants from birth to 18 months of age. Primary HLH refers to presence of an underlying genetic disorder and secondary HLH refers to HLH phenomenon occurring secondary to another condition (ex viral illness) has caused a great deal of confusion among clinicians. Yet, the clinical presentation and outcome of both are generally the same.

HLH is associated with a many different infections, autoimmune disorders, and malignancies. The different amounts of infections associated with HLH include:EBV, CMV, parvovirus, herpes simplex, varicella-zoster, measles, HHV-8, and HIV. HLH may occur shortly after the initiation of HAART in the treatment of HIV-AIDS. HLH may also correspond wihth some bacterial infections(Brucella, gram negative bacteria, tuberculosis), parasites (Leishmaniasis, and fungal infections.

Autoimmune disorders associated with HLH include lupus, rheumatoid arthritis, Still’s disease, polyarteritis nodosa, mixed connective tissue disease, pulmonary sarcoidosis, systemic sclerosis, and Sjogren’s syndrome. HLH can also be found in patients with immune deficiencies such as X-linked lymphoproliferative syndrome, in renal or liver transplant recipients, or Kawasaki disease.

The basic pathophysiologic abnormality in HLH is cytokine dysfunction leading to accumulation of activated T-lymphocytes and activated histiocytes (macrophages) in many organs. The cytokines that are found in high levels in the plasma of HLH patients include interferon gamma, TNF-alpha, interleukins (IL-6, IL-12, and soluble IL-2 receptor (CD25). There has also been evidence of depressed or nonexistent natural killer cell and cytotoxic activity in HLH patients and family members. Their natural killer cell activity sometimes returns to normal when patients are in remission. Genes on chromosome 6,9,10, and 17 have been reported to be associated with HLH.

The initial symptoms and signs of HLH are similar to common infections, fevers of unknown origin, or hepatitis. Thus the diagnosis of HLH may be made late in the course of the disease or postmortem. In a Swedish study, the following symptoms were found most patients (they listed in order of most common): fever, hepatomegaly, splenomegaly, neurologic symptoms, rash, and lymphadenopathy. Many of these patients have clinical and radiologic findings similar to someone with acute respiratory distress syndrome. Thus alveolar-interstitial opacities and pleural effusions are common. On ultrasound, you may find gall bladder thickening, hyperechoic kidneys, ascites, and hepatomegaly. Patients may also have a mononuclear pleocytosis of the cerebral spinal fluid (lymphocytic meningitis) and evidence of parameningeal infiltrations, subdural effusions, retinal hemorrhages, and hypodense or necrotic areas, demonstrated by MRI of the brain.
On pathology, may see proliferation of normal histiocytes and T-lymphocytes in various tissues. There may also be hemophagocytosis of red cells, other WBCs, and platelets in the bone marrow, spleen, or lymph nodes. Infiltration of the liver and bone marrow with histiocytes and the antiproliferative effects of cytokines leads to damage to these organs. Hepatic failure is a common feature of HLH patients. Such patients may also have hyperbilirubinemia, hypoalbuminemia, and decreased number of clotting factors.

Diagnosis of HLH takes a high level of suspicion. The diagnostic criteria is defined by a set of major signs and symptoms which are as follows: fever, splenomegaly, cytopenia in at least two cell lines, hypertriglyceridemia and/or hypofibrinogenemia, and tissue demonstration of hemophagocytosis. Additional criteria include low or absent NK cell activity, serum ferritin concentration >500 microg/L, and soluble CD25 (sIL-2 receptor) >2400 U/mL. Either the first of these three additional criteria or a combo of the second and third may replace one of the major criteria listed previously.

Treatment of HLH involves initiating immunochemotherapy on the HLH-2004 protocol. This protocol includes induction therapy with dexamethasone, etoposide (VP-16), cyclosporine (started at week 9), and intrathecal methotrexate, followed by pulses of dexamethasone and VP-16 for up to one year. Allogenic hematopoietic cell transplantation appears to provide the best overall cure rate in HLH patients. This therapy is needed in all patients who have homozygous mutation in the various genes associated with HLH, those who have responded poorly to the initial eight weeks of therapy, and those with CNS disease. The protocol should not be used in patients with the following: systemic juvenile rheumatoid arthritis and lupus patients with the macrophage activation syndrome, HIV-associated HLH, and iatrogenically immune-suppressed patients.

References= http://www.uptodate.com/

Pictures:
1)While in Bombay, we drove by a traditional Hindi wedding. This was the groom on his way to get his bride. The ceremony looked beautiful.
2) Me on Marine Drive.
3) This is Jantar Mantar. This is an observatory began in 1728. It is basically a place with a bunch of sundals, compasses, and astronomy stuff. This area has an instrument used to locate your birthday sign. I am standing next to the Gemini section.
4) City Palace is the home of maharaja of Jaipur. The family still lives there, but that area was off limits. The guys in the picture wanted me to take a pic with them then they asked for money. That was the last person I took any pics with that wasn't from the US.
5) In a shop in Jaipur. The guy in the store wanted to show us how to wear a sari. In the Rajasthan area, the women wear a part of the sari material over their head. In other areas of India they just drape it over their shoulder.These fools also wanted me to take a pic with them then they asked for money. That was the last person I took any pics with that wasn't from the US.
6) Erica and I trying on saris at a local shop in Jaipur.
7) This is me and Erica riding an Elephant. This is a professional shot that some guy took for us. I was glad to know that they only make the elephants carry tourist up to the fort 5 times a day then they get to rest until the next morning. I was still bothered by the stick the guy used to beat the elephant into staying in line.

8) This is the view from on top of the elephant at Amber Fort in Jaipur. The elephant kept on blowing its nasty boogers on us. That got annoying. But it was still really cool to be seating on top of an elephant.

9)This is the Water Palace in Jaipur. We got to look at it from a distance. I wonder how they built this thing?