One Shoe Drops

The most frustrating thing about the last couple of weeks has been seeing test after test coming back “negative”. None of the garden variety pathogens that could be causing Harvey’s high fevers was triggering. As I wrote in the last post, it is hard fighting an unknown enemy. The docs were loading Harvey up with multiple broad spectrum antibiotics and high dose acyclovir in the wan hope that if you throw enough stones one of them may hit the unseen object. That was not a successful strategy and I worried as Harvey’s symptoms got worse. In addition to the daily fever (sometimes as high as 103.5, in spite of Tylenol and Advil to try and control it) the pain he felt in his upper right abdomen was getting worse.

Finally, with all of those snares out there, we caught something in the nets of testing and re-testing. It appears Harvey has CMV (cytomegalovirus) reactivation. They routinely monitor the number of copies of the virus present in the blood. Anything under 100 is considered negative and that was where it was for weeks. Suddenly, the latest CMV viral titre showed positive, with a viral load of 2,500 – above the actionable level of 400 copies. Just to reassure our friends out there, viral titre of 2,500 is definitely actionable but not all that high. Many patients present with much higher viral counts at diagnosis.

Is this the whole story, does it explain all of the nasty symptoms that Harvey has been experiencing? Is this the only shoe that was going to drop, or do we have to wait for the second or even third shoe to drop? I do not know. If I were to guess, I would think (hope) that a combination of CMV reactivation plus incipient GVHD just getting started will cover the waterfront and there are no other bad guys out there causing trouble. Only time will tell if I am right.

Cytomegalovirus

Here is some background information on CMV. The majority of transplant patients as well as CLL patients who have been treated with T-cell suppressing therapies (Campath is infamous in this regard) have reason to be wary of this member of the Herpes family. Kids get infected with it as toddlers in developing countries, where as the infection seems to take place more frequently among young adults in developed countries. In healthy people the initial infection is most likely never even noticed since it has few symptoms. But once infected, the virus remains in the body for the rest of the life of the host, to raise its ugly head during periods of immune incompetence. It is a major risk factor for HIV patients, solid organ or bone marrow transplant patients, or just about anyone with less than competent immune surveillance.

CMV reactivation in immune compromised people can damage almost any organ in the body. It can cause the ever popular “Fever of unknown origin”, pneumonia, hepatitis, GI tract problems, genitourinary system problems, eye problems, neuropathy – the list goes on. The gold standard for detection of CMV in blood or tissue is the PCR (polymerase chain reaction) technique.

The body’s best defence against CMV virus is T-cell mediated attack. That explains why people without T-cells (or badly compromised T-cells, as in AIDS patients) are so vulnerable. Part of the deal in stem cell transplants is controlling T-cells, immune suppressants such as Gengraf (cyclosporine A) and Prograf (Tacrolimus) are used to keep the pesky T-cells from growing too fast in order to limit high grade GVHD. The other side of this coin is that patients may be a tad low on CMV fighting T-cells as well. As I said before, it is a careful game of chicken – a balancing act that takes nerves of steel.

How They Treat CMV Reactivation

CMV is a virus, as its name implies, and therefore it cannot be controlled by antibiotics. Garden variety anti-virals such as acyclovir (brand name “Zovirax”) famciclovir (“Famvir”) used to control Herpes Zoster and Herpes Simplex are less than effective against CMV. This particular member of the Herpes family needs ganciclovir (“Cytovene“), usually via intravenous infusion. Taking ganciclovir tablets is not all that helpful since only a very small percentage of the drug gets absorbed into the blood. A somewhat more effective oral version of the drug is available, called valganciclovir. Two other drugs that are also used to fight CMV infection are cidofovir (“Vistide”) and foscavir (“Foscarnet”).

None of these drugs are exactly friendly. All of them are myelosuppressive, causing the gradually increasing white blood counts to take a big hit. All of them are excreted in the urine by the kidneys. If the load on the kidneys is already high (as demonstrated by a high creatinine level), than the body is not as efficient in getting rid of the antiviral drug and its concentration can get to be quite high. Transplant patients take a lot of drugs (see our earlier post on “Better living through chemicals”) and the kidneys and liver are not exactly underutilized. What this means is that creatinine level is carefully monitored each day and ganciclovir dose adjusted accordingly. Higher creatinine levels signal things are getting backed up in the kidneys and lower drug dosage is indicated to keep the level in the blood from getting too high. I am impressed how seriously Fairview Hospital takes dosing levels of ganciclovir.

I am told most varieties of CMV (yes, there can be many subtle variations on the theme of this particular virus) respond quite well to ganciclovir. If that fails, the back up game plan is to use Foscarnet or Vistide. I get the sense that they are more quick to use any of these drugs in cases of adult donor stem cell transplants, since the large dose of transplanted stem cells from the adult donor means a more robust graft. Cord blood transplanters are a bit more skittish of using any of these three drugs without sufficient cause to use them. Frankly, I too am a big fan of less-is-more when it comes to drugs.

One last interesting therapy option for treating tough to control CMV infection is a blood product called Cytogam. Most of us are familiar with IVIG therapy, intravenous infusion of immunoglobulins collected from pooled blood donations. These immunoglobulins represent the combined disease fighting capability of the pool of donors whose blood went into its making. Think of it as very broad spread shot-gun pellets, able to hit a large number of target pathogens, whatever the blood donors had encountered in their community. Cytogam is different. It too is an immunoglobulin isolated from donated blood. But it is a specific and very directed immunoglobulin against the CMV virus. I am quite intrigued by this product, but its use thus far has been quite limited due to (a) very high price (b) massive supply bottlenecks. I think the company has solved the supply issues, but not the high price. Perhaps in future we will see increasing use of this “smart” bullet approach to controlling CMV infections. I sincerely hope so.

How is Our Hero Doing?

I am cautiously optimistic that Harvey is benefiting from the ganciclovir therapy. So far he has been on this potent anti-viral for 3 days. The game plan is to continue the infusions for a full 2 weeks, after which he may be weaned off to the oral variety. I think I see a downward trend in the fever that has become a fixture every evening for the past couple of weeks. We are cutting back and no longer need maximum daily doses of Tylenol and Advil. (While Tylenol and Advil are both fever reducers, they work by different routes and have non-overlapping toxicities. That is why it is sometimes recommended to take both drugs in combination, rather than exceeding safe limits on either one by itself. Please remember Tylenol in large amounts can cause significant toxicity, too much of it can permanently damage your liver, or even cause death). Harvey tells me the pain in his midsection is getting better as well. Sure enough, ganciclovir is suppressing the WBC (white blood count) and ANC (absolute neutrophil count) and Harvey needs Neupogen shots on alternate days to keep the counts in healthy region. Hopefully this will not be needed as they taper off the ganciclovir dose.

Have we dodged this bullet? I think so. Perhaps I should not jinx myself, perhaps I should say instead “I hope so”. In any case, ganciclovir is very potent virus killer and if there were other viral culprits lurking in Harvey’s body that had not yet been identified, there is good reason to hope we are killing all of them. For example, the HHV6 repeat testing results indicated this particular nasty has gone back into its lair, its counts are now below detection threshold.

For all of you who posted your comments on the prior entry as well as those of you who wrote to us directly, thank you for your support and love, from the bottom of our hearts. It would have been a lot more scary and lonely but for the affection we felt from so many generous people.

Be well,

Chaya