FHL, or, Familial HLH

Now that I’ve attempted to lay out some basic information for understanding HLH, I’d like to take a look at the real issue: the difference between FHL and HLH.

When I began reading up on this disease it took quite some time to understand where FHL, or Familial HLH, fit in to the picture. When literature or doctors talk about the disease, they tend to refer to it simply as HLH. Over time I’ve come to realize there are a variety of reasons for this, not least of which is the difficulty in diagnosing which of the forms of HLH a patient has. So, let’s take a look at the two forms side by side.

HLH, or Hemophagocytic Lymphohistiocytosis, is the name for the immune disorder. It can come in one of two forms: Familial HLH, also called FHL, and Acquired HLH, usually referred to simply as HLH.


  • Is the primary, or most common, form of HLH
  • Is also known as Familial HLH
  • Is caused by a genetic defect passed to the child by parents who are carriers; children of parents who each are carriers (as they must be for the child to have the disease) have a 1 in 4, or 25%, chance of getting FHL.
  • Is rare for two reasons primarily: because it requires two parents who both carry the recessive genetic defect to mate and pass on the gene (only a 25% chance); and because it goes undiagnosed often enough with 100% fatality, so as to seem more rare than it likely is.
  • Is generally found in very young children; this is because it manifests itself when the child has an immune response (such as to a cold) and once it manifests is fatal if untreated. Kids who have FHL get sick as kids always do at some point, and they don’t survive unless treated. So, it’s not usually found in older kids — it’s either treated successfully or it is fatal.
  • Is fatal if uncured. This means that the disease can be put in remission temporarily through the HLH-2004 protocol, but will return worse and likely with fatal results if uncured.
  • Can only be cured with a Bone Marrow Transplant, or a Stem Cell Transplant.
  • Requires genetic testing to positively confirm


  • Is the secondary, or less common, form of HLH
  • Is also known as Acquired HLH
  • Is caused by an immune disorder resulting from another condition putting the immune system under severe strain
  • Patients who have HLH are usually slightly older children (>1yr), though it has been seen in infants as well
  • Is able to be treated successfully with HLH-2004, and often resolves itself permanently once it and the underlying condition are treated
  • Cannot be positively confirmed through genetic testing

The Diagnosis Problem

HLH, in either form, is rapidly fatal. Within two months of the disease manifestation, an untreated (undiagnosed) child will die 100% of the time.

Therefore, diagnosis of the particular form of the disease is not the most pressing issue, but instead the focus is on treating the patient as soon as possible to control the immune response before it destroys the body.

Once the disease is under control, a determination has to be made as to whether a Bone Marrow Transplant (BMT) or Stem Cell Transplant (SCT) will be needed. This is where it really gets tricky, and why distinguishing between the two forms is so vital. FHL requires a BMT/SCT to be cured, whereas Acquired HLH does not.

Both BMT and SCT are highly dangerous procedures, not due to the transplant itself but to the difficulty the patient has with accepting the new cells and surviving the side effects. Survival rates for children appear to be in the neighborhood of 70%, with some variation depending on the type of transplant cells used. The numbers never look “good” though, for these procedures — the risk is always too high.

Therefore deciding to get a BMT or SCT is a tough decision, and unfortunately diagnosis of FHL is not always able to be positively confirmed. What has to happen is the tests must be done, and the overall picture must be looked at.

Factors that are considered:

  • Results of genetic testing: Sometimes will positively confirm the disease, however because we do not yet know all of the genes to test it does not always confirm it
  • Results of Soluble IL-2 test: Over 10,000 tends to be a marker for FHL
  • Results of NK cell count test: Low or absent counts are a marker for HLH in general, but not specifically FHL or HLH
  • Age of the patient: due to the manner in which Acquired HLH manifests, very young patients without an underlying condition tend to be assumed to have FHL

It is unfortunately not possible to positively confirm Acquired HLH, only FHL. Therefore, to make a decision the doctor and parents will need to look at all of the information and test results before deciding on the need for the transplant.

Click to enlarge

Here is a chart sometimes used to understand the process for diagnosing FHL. Please note: HCT is the acronym for the medical term for Bone Marrow or Stem Cell Transplant

HLH: A Simple Description

In order to properly discuss or write about some of the more complicated aspects of this disease, I feel I need to try and post as simple an explanation of it as possible. It’s not as simple as I would like because it’s such a complicated set of problems, but I’ve tried to include the basic facts everyone interested should know.


  • HLH is a rare disorder of the immune system. It is also commonly referred to as a disease. It’s rarity is currently understood to be approximately 1 in 1 million children as many as one in 50,000 children, with recent studies suggesting it is even more common than previously believed.
  • There are two forms of the disease. The primary form is FHL, also known as Familial HLH. The secondary form is simply known as HLH. Both forms are treated in the same manner medically, with the exception of the additional need for a Bone Marrow or Stem Cell transplant to cure the primary form.


  • When the body has an infection, certain specialized cells activate and fight off the infection. These cells are part of our Immune System. Among these cells are T-Cells and Histiocytes, which when activated cause an inflammatory reaction in the body.
  • In most people when an infection(a cold, flu, other virus or a bacterial infection for example) has been eliminated, the inflammatory reaction that helps eliminate them is turned off and the Immune System returns to it’s “Steady State” or normal state. In HLH patients, the inflammatory reaction does not turn off and causes the symptoms of HLH.
  • Our Bone Marrow produces our blood cells, including infection fighting cells. As the inflammation persists abnormally, the Histiocyte cells attack or “eat” the other blood cells in the bone marrow, causing a severe drop in cell counts. This means that the patient is exposed to normal infections, but has no way to fight those infections off.
  • Typical symptoms of HLH itself can include: Fever, Pallor, Jaundice, Liver and Spleen enlargement, and Neurological symptoms such as irritability and seizures. Not all symptoms appear in all patients initially.
  • Because symptoms vary widely and can be associated with other infections, HLH is very difficult to diagnose. It is an especially dangerous disease undiagnosed, with a fatality rate of 100% over a course of approximately 2 months. 100% of patients will die in 2 months if untreated.
  • Patients have a better chance of survival of this disease the earlier they are diagnosed and treated. The longer the disease continues, the more damage the body does to itself. Because the treatment itself is hard on the body and the disease often affects young children, if the body is too badly damaged, recovery can be difficult even when treated properly.


  • HLH is currently treated with a protocol or treatment program called HLH-2004. This program was created by an international team of doctors in 2004 to attempt to address the poor survival rates of patients with HLH. Prior to that point, a program known as HLH-94 was used.
  • HLH-2004 involves a chemotherapy regimen (a set medicines given to the patient) to stop or suppress the inflammation in the body, bringing the disease under control.
  • Once the disease is under control — once the immune system has “cooled off” — symptoms can begin to fade and the patient’s immediate danger from HLH itself is lessened. The patient is still at very high risk from normal infections due to the damaged immune system.
  • Infection presents the greatest risk to patients with HLH after it has been diagnosed and treated.
  • In the primary form of HLH, known as FHL, remission is only temporary. A Bone Marrow or Stem Cell transplantation is required for long term survival.
  • In the secondary form of HLH, the disease can be permanently resolved with the HLH-2004 program in some cases.

The question many parents want an answer to most, “what are our chances”,  is very hard to answer. I know I spent a lot of time trying.

That answer is there is no easy answer. It depends strongly on how early diagnosis and treatment took place and what underlying conditions are present. In short: your doctor should be the one to even try to answer that because it really is dependent on the unique situation of each child.

More information is available at Histiocyte.org as a starting point. I’ve posted articles I’ve found to be useful in the Links section above as well.

The Horrible Very Bad “NPO”

Nil Per Os: A Latin phrase which means, “nothing through the mouth”

Outside of the truly bad things, those three little letters have come to foreshadow more anguish and suffering around our household than most any other.

Don’t feed your baby. Don’t feed your baby.

It’s really hard to get that through the head, and even harder after a few hours of listening to her fuss about it. With an older child, I’d imagine you can explain somewhat, but Zoe only wants one thing at this point, and she just doesn’t understand when she doesn’t get it.

We’re due for Zoe’s new line to be installed today. We spoke to Dr. W and had the actual VP-16 moved back a day to our and her relief, so that she is not getting it right on the heels of the surgery and well into the night. In order to have the surgery though, Zoe has to have her anesthesia, and of course this means that little card appears with the dreaded NPO on it.

We have some confusion as to when the NPO is to start, and a little frustration as a result. Michelle was told initially 12am on the phone, with a surgery scheduled for 12pm. That’s 12 hours without food for a child who eats every 2 hours normally. A little harsh? You would think so. The nurse specifically said no milk or formula, even though the 12am time is typically for solid foods.

The point of confusion is that we were told 4 hours on Monday by the surgeon doing the procedure, and we tend to want to trust that number more.

So to try and resolve it, I call in, explain who I’m calling for, and that I need clarification on the NPO. “How long before the surgery do we need to wait to feed her?” 12am. I explain that Zoe is 3 months old, and immediately the response is “oh, well the NPO is more for solid foods she can have fluids up to five hours before.”

I feel sure that whatever information is available to whoever is making that decision must indicate her age. Surely. If it is, I wish that they would give us the 5 hour number up front.

After a little more back and forth, we clarify that it’s technically 4 hours, but they tack on an extra hour in case they want to move up her surgery, and the NPO is pretty much always set for 12am the day before surgery. Does it matter if it’s an infant? Technically yes, but in practice, no. They put what they put and it’s again up to the parent to push back and get the exact information, lest they suffer through needless additional hours of crying inconsolable baby stress.

Early in our stay at the hospital, for her first Broviac, this same thing happened exactly — one person told us 4 hours but someone else said midnight, we played it safe and went with midnight, and the result was a horrible experience for Zoe and Michelle and I. At that time Zoe’s blood pressure and heart rate were a concern, since she was still fighting back from her initial fever, yet still she was put on a 10-hour NPO crying and amping up her stress all night.

This time, we knew better. Progress!  And, now Zoe and her parents will get to sleep tonight instead of living the horror movie that is an unfed baby.

Update: Zoe is done with surgery, all went well. She was very very hungry by the time of it, and let everyone know.  As feared however, we did not actually get in there until 2pm.

I completely understand the difficulty in lining up multiple departments at one time to get the Surgeon, Anesthesiologist and Oncology NP in at the same time, but it feels like there must be a way that doesn’t involve infants going unfed for 7-12 hours routinely. At the very least making sure to distinguish between solid fed and breast/formula fed children seems like it would be a good idea.

Never a Dull Day

Well, we headed into the hospital for our routine blood draw for CBC and vitals, and ended up in there an extra 3 hours.

Typically the way the blood draw works is this: the nurse flushes her Broviac line with Heparin to prevent coagulating, and then with part of a syringe of saline. Once the saline is in, they start to draw back on the plunger and see if any staining happens, meaning blood is in the line and ready to be drawn. That’s the goal.

Instead, we often end up pushing an entire syringe of saline in, then go through a dance where Michelle or I move Zoe’s limbs up and down, pumping her like a little old fashioned water well, or roll her over and around trying to find a position where the blood will enter the line.

This isn’t the way it should be, but we have just learned to deal with it. She’s very small and so is her line.

Today, we did exactly that, except there was no staining in the saline, no matter what we tried. The nurse proceeded to push a 2nd syringe of saline in, and still nothing showed. She pumped the syringe for awhile, and then one of us pulled Zoe’s shirt back, Michelle I think, because she noticed some liquid. Turns out the saline was escaping the line and Zoe now had a huge bubble of fluid boiling up under her skin just above the Broviac.

Now, we’ve come to have a decent level of calm in these visits, but this was a real challenge. The lump was really big and quite startling. It was a reminder of how quickly something can happen and upend our sense of calm, potentially putting us back in the hospital unexpectedly.

My first thought was not pretty — I was a little irritable at the amount of saline pushed in so quickly — but I’ve learned to restrain myself a little to wait and see how the doctors react before reacting too strongly myself. We stopped the attempted blood draw, got the doctor in, and had a look. Her first remark when she saw my face was, “oh don’t worry it’ll be reabsorbed, she’ll be ok”. I would have liked to see my face just before she said that, I’m sure it was priceless.

Soon we were settled in a room waiting for the surgeon to come take a look. When he arrived an hour later the bump had disappeared, the fluid absorbed. He reassured us that the Broviac issue was  not something to be terribly concerned about, but that we would want to put in a new line. It’s necessary not only for easier blood draws, but for administration of Zoe’s VP-16 chemotherapy.

This line was no longer needed, however. So what do we do? Pull it out. Right there on the little exam table, let’s yank out the direct line into her heart that took a 2hour procedure and anesthesia to put in!

I would never have been cut out for medicine, I realize now. There is an old wives tale about fathers passed out on the floor of the hospital whenever there is blood, and I’ve begun to wonder if it’s not a wives’ tale so much as a cautionary story.

The removal went fine, of course, the surgeon was not concerned and I’m sure he pulls tubes out of babies hearts all day long, but boy it was a little nerve wracking on our end. He held a bandage over the hole in her chest for a few moments, announced it was all set, and they applied the new dressing. Apparently it closes so quickly there is not need to worry about blood leakage or other problems. What a relief!

We’re on track for another long day on Thursday, Zoe will get her LP, her new Broviac, and a four hour drip of VP-16.

Vitals for the day:

  • WBC: 2.4
  • RBC: 3.0
  • Hemo: 9.0
  • Platelets: 613
  • Sodium: 132 (a little low still)
  • Creatinine: .1 (normal is .3-.7, this is a marker for kidney function and the doctor felt it was fine)

The Thursday Routine

Each thursday for awhile Zoe will be headed into the outpatient clinic to get her LP (spinal tap), her Etoposide dose, and her blood draws. This complicates her day quite a bit. Here’s a look at her routine for the day:

  • 4am, last feeding for the morning in advance of Zoe’s “8am” surgery appointment
  • 6am, Zoe wakes and starts to fuss for her breakfast, won’t go back to sleep due to hunger. This is very nearly the worst part, listening to a crying baby and not being able to soothe her fully causes me to break out into a sweat almost instantly
  • 7am, we’re up fully now and starting to prepare her meds for the morning
  • 7:20, Zoe takes her meds. We held off on giving cyclosporine because they’re taking her levels in a couple hours — giving a dose on top of a blood draw results in an incorrectly high reading. We also skip her 2nd blood pressure me, the Atenolol, since she’s due to go under anesthesia shortly and we’re scared having two BP meds on top of that might be dangerous. Zoe eats her meds much more easily than usual; there’s something heartbreaking about a baby who takes her meds greedily because she can’t eat.
  • 8am, we’re at the clinic; Zoe gets a blood draw once we’re in the room but her Broviac/central line is so small that it doesn’t give up blood easily — we have to pump her little arms around and roll her back and forth until they get enough blood for the tests. At least she’s getting her exercise.
  • 9am, Dr. M is back, stops by to take a look at Zoe. He’s encouraged by her counts and says that her fussiness, puffy cheeks and hunger should start to drop as we continue to drop the steroid dosage; he advises us we were quite right to skip the 2nd BP med, which is a relief
  • 10:15, they finally come to pick us up for Zoe’s procedure; we were first in line we’re told but I imagine they took care of someone else while we were getting blood draws and the exam
  • 10:45, they start the Lumbar Puncture procedure; the anesthesiologist confirms she hasn’t had anything to drink since 4 and we discuss which meds she took this morning to be sure they know about skipping the 2nd BP dose
  • 11am, it takes 3 sticks in her back to get the LP done; it’s terrifying, no other word comes to mind
  • 11:15, they tip her head down at a shallow angle on the table so that the medication introduced into her spinal fluid can flow down and fully saturate the area around the brain; the goal here is to ensure those few histiocytes they’ve seen in her spinal fluid don’t have a chance to collect in her brain, the medication should suppress them
  • 11:30, we’re moved to observation for Zoe’s VP-16/Etoposide dose for the week
  • 12:30, while on the VP-16 drip Zoe’s face flushes; we’re concerned as to why, she appears to be asleep peacefully on the dregs of the anesthesia; the doctor takes a look, feels it’s her steroids — no other signs anywhere, pulse/o2 is good and bp is 92/44; VP-16 resumes.
  • 1pm, flush is worse, Zoe is an angry red now so we call in the troops; VP-16 is paused and they administer a dose of Benadryl — the determination is to wait 15min and if her color is the same or improved, we resume VP-16 at half speed. This means we’ll be here an additional 2.5 hours to complete the drip.
  • 1:30, Dr. M stops back by to discuss Zoe’s counts. He seems really optimistic and happy about them, more so than ever before. Almost everything has improved but in particular her WBC count has moved out of the infection danger zone, meaning Zoe is a little safer day to day now.
  • 2:15, flush is completely gone. Benadryl is some amazing stuff.
  • 3:30, VP-16 complete, the long day is nearly over; a little stomach upset that seems to pass after a few diaper changes over about 15minutes
  • 4pm, we change Zoe’s Broviak dressing; the process for this is fully sterile, meaning a sterilized dressing pouch and a simple ritualistic routine to ensure no contaminants get near her line opening
  • 4:30, home again; Zoe wants nothing more than to sleep, we settle her into bed for a nice nap
  • 7:30, meds again, and more sleep to round out the long day

It’s strange at the end of the day to realize that we spent a full “work” day in the hospital managing this, Michelle and I. I don’t know how any family could do this without support, it’s really quite daunting. The reward is that Zoe looks beautiful and calm come bedtime. Progress.