HOW TO FIGHT A FUNGAL INFECTION: Part 1 Medication

How fungal spores enter the sinus and lungs.

Fungal infections were new to us.  We knew of them, since before and after Todd's first allogeneic bone marrow transplant in September 2014, but fortunately, Todd had never had one until now.  There was so much we needed to learn. 

At first, we were told that they are 1) hard to fight; 2) can take weeks or months to get rid of; 3) can be invasive and can spread.  This is why it took so many tests: x-rays, CT scans, and MRIs, and the biopsy to confirm the diagnosis.  If left untreated quickly, it can be deadly.

One of the better articles on the subject is and is referenced at the end of this post.  If you are going to any reading beyond this blog on the subject, I would recommend it as a starting point.  I want to pause here to include an interesting paragraph:

The increase in the incidence of IFI has resulted in a substantial increase in the length of hospital stays and healthcare expenditures [Morgan et al. 2005; Dasbach et al. 2000]. As an example, compared with cancer patients without aspergillosis, cancer patients with this disease stayed in the hospital for an average of 26 more days (33 vs. 7 days), incurred US $115,262 more in total costs on average, and had four times the mortality rate during hospitalization (31% vs. 7%) [Dasbach et al. 2000]. (Bhatt, Viola, and Ferrajoli, 2011, Epidemiology, par. 3).

The reference made here that an increase in Infectious Fungal Infections (IFI) is due to the "increasing frequency of infection by non-Aspergillus molds (e.g. zygomycosis) and the emergence of drug-resistant fungal pathogens." (Bhatt, Viola, Ferrajoli, 2011,Abstract).  I also found it interesting, in this one example, that the cancer patients stayed an average 26 more days in the hospital.  Todd was diagnosed solely on a fever and a little jaw/facial pain.  He was admitted on November 5, 2016 and we are hoping he will discharged on November 29, 2016, a total stay for 24 days; uncannily close to the 26 days in this example!

Treatments

I wanted to discuss the three types of treatment used to treat fungal infections: antifungal medications, hyperbaric treatments, and white cells.  In Part 1 here I will explore the first treatment:

1. Heavy duty antifungal medications for long period of times.

They can try to give specific antifungals if they can determine the type of fungus, but this often takes weeks for anything to grow in a culture.  In Todd's case, one of his cultures grew a Penicillium fungus used to make penicillin, however, it is extremely rare for this to actually be the type of fungus found in the sinuses.  It is usually only contracted in Eastern Asian countries like Thailand, northeast India, China, etc. (Chen, et al. 2013, n.p.).  So, the infectious disease doctors were very skeptical that this type of fungus grew from the biopsy of Todd's sinus.  Instead, they think it came from a contaminate from the lab that landed onto the petri dish and grew.  The most common strains come from molds and yeasts and are too numerous to recite here.  While Todd was already taking  a prophylaxis or preventative antifungal medication like Voriconazole while his white counts and ANCs were at zero, it wasn't enough to keep him from getting a fungal infection. 

The million dollar question: How did he get it? 

It is likely that he got the infection from simply breathing spores in the air that everyone typically breathes in.  Normally, it wouldn't bother a healthy individual, but for immunocompromised patients like Todd, it can be dangerous.  Todd does however, fall into the "High Risk Groups" (click link), in three categories: those with "Severe neutropenia (ANC) <0.1 × 10⁹/l for >3 weeks," those with use of "Corticosteroids >1 mg/kg and mild neutropenia (ANC <1 × 10⁹/l) for >1 week" (used to prevent reactions to transfusions), and has had "High-dose cytarabine or fludarabine" (used in the first leukemia induction chemotherapy. (Bhatt, Viola, and Ferrajoli, 2011, Table 1).

They had to change his IV anti-fungal medications a few times, but finally resolved on a course of the very strong Amphotercin B, also known as AmBisome, given by daily 425 mg intravenous infusions.  According to the Wikipedia entry on Amphotercin B, it is used in "a wide range of systemic fungal infections," (Wikipedia, par. 4) and is often "the only effective treatment for some fungal infections." (Wikipedia, par. 1). So, apparently, it is the "go to" antifungal medication.  It does have some nasty side effects.  The first is called the "shake and bake" which is basically the chills and shakes.  Todd never had this side effect; he has only got hot and sweaty.  The side effects that Todd did have though were bad enough.  He had chest tightening and a painful pulse in his tailbone.  They doctors were finally able to get around this side effects with the use of three pre-medications: Tylenol, hydrocortisone, and Benadryl and by running the IV pump at a very slow rate over 4 hours. Apparently, he will have to receive AmBisome IVs everyday or every other day even after being discharged, on an out-patient basis or I may even have to give him the infusions at the hotel/apartment. 

Why the sinus?

According to a journal article published by Bhatt, Viola, and Ferrajoli, sites of fungal infections included lungs, orbito-sinus-facial structures, and cerebral regions. The statistics were as follows:

In a study of patients with hematologic malignancies, the most frequent sites of mucormycosis were the lungs (64%) and the orbito-sinus-facial structures (24%), while cerebral involvement and disseminated infection were observed in only 19% and 8% of the cases, respectively [Pagano et al. 2004]. (As quoted in Bhatt, Viola, and Ferrajoli, 2011, n.p.)

It is such a nasty infection, that certain types can spread to the face, the eye, the brain, and even the skin.  We were always concerned with the questions from doctors regarding pain in his face, differences in his vision, and the full body inspections looking for fungal infection on the skin.  Todd decided to Google photos of invasive fugal infections and here are a few of the photos he found on what they can do.  TODD DOES NOT HAVE AN INVASIVE FUNGAL INFECTION LIKE THESE PHOTOS!  His was caught very early.  This is what they can do:

Invasive Fungus Sinusitis: Medscape 2000

Fungal Infection in Eye/Orbital

Mukherjee, B., Raichura, N., Alam, M. 2016.

Fungal Skin infection (mild): No JH, Yu JS, Kim EO, et al. 2010

Todd's fungal infection started in his sinus as a sinusitis, but then dropped into his lungs.  Fungal pneumonia shows up in a unique way in lung x-rays and scans by exhibiting itself in nodules. It is treated though in the same ways. 

You can understand the doctors concerns with fungal infections and treating them quickly and thoroughly!  Todd is very fortunate that his was caught extremely early! 

Besides antifungal medications, the doctors have seen some success with hyperbaric treatments.  I will explore this treatment in the next blog post.

References: 

Amphotercin B, 2016. Wikipedia.  Web.  Retrieved from:

https://en.wikipedia.org/wiki/Amphotericin_B

Bhatt, V., Viola, G, and Ferrajoli, A.  Ther Adv Hematol. 2011 Aug; 2(4): 231–247. doi: 10.1177/2040620711410098 Web. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573411/

Chen, M., Houbraken, J., Pan, W., et. al. BMC Infectious Diseases 201313:496

DOI: 10.1186/1471-2334-13-496. Web. Retrieved from: http://bmcinfectdis.biomedcentral.com/articles/10.1186/1471-2334-13-496

Medscape General Medicine. 2000;2(1) "Fungal Sinusitis." Web.  Retrieved from: http://www.medscape.com/viewarticle/408751_2

Mukherjee B, Raichura ND, Alam MS. Fungal infections of the orbit. Indian J Ophthalmol. [serial online] 2016 [cited 2016 Nov 27];64:337-45. Retrieved from: http://www.ijo.in/text.asp?2016/64/5/337/185588

No JH, Yu JS, Kim EO, Choi HH, Kim SH, Kwon JC, Lee DG, Choi SM, Park SH, Choi JH, Yoo JH, Kim HJ, Min WS.   A Case of Disseminated Aspergillosis Presenting Solely as Multiple Cutaneous Lesions in an Acute Leukemia Patient.   Infect Chemother. 2010 Aug;42(4):244-248.   https://doi.org/10.3947/ic.2010.42.4.244

TODD ADMITTED BACK TO HOSPITAL AFTER KIDS ARRIVAL TO HOUSTON

Group Picture: Picking up Ellie and Lewis at Hobby Airport, Houston

On Saturday, November 5, 2016, Todd woke up with a fever at the hotel!  We were planning on picking up two of our children from the airport for a weekend visit.  I started to take him to the emergency room, but after an hour, it went down.  He insisted on going to the airport with me anyway, but he felt so poorly that I had to wheel him in with his mask on.  The kids arrived and we were so happy!  We got a quick bite to eat, but Todd didn't feel like eating.  I was still concerned and make him pull the thermometer out of his jacket pocket to take his temperature.  He got sweaty and the fever seemed to break for good.  I took him back to the hotel while I took Ellie to the store.  When I got back, I noticed right away that his cheeks were red.  I asked if he was running a fever and he said yes.  I had already packed a suitcase for him earlier that morning and had it in the car just in case.  So we hugged the kids and were off to the ER.

Of course, they got him into a room and said that they were planning on admitting him.  They worked quickly to try to find the source of the fever: blood cultures, chest x-ray, urinalysis, etc.  When the doctor came in I told him I had been concerned that he had 0 platelets, which worried me about bleeding in the brain, or that he had an abscessed tooth from one of those cavities in his wisdom teeth.  He asked if Todd has had a scan of his head since we arrived or even recently, and I said NO!
So he decided to do a CT of the head. 

Sure enough, it was the CT scan of his head that showed a sinusitis infection in his right sinus.  This was not what I expected, or what they were looking for, but I guess it was a good thing that they did it.   The chest x-ray looked ok at this time.  After they got Todd into a room on the Leukemia Floor, I stayed until after 10 p.m. and drove back to the hotel to stay with the kids.  Of course, he needed blood and platelet transfusions too.  Luckily, I had called Todd's cousin Denise who lives in nearby League City earlier in the day asking her to help with the kids if I needed to take Todd to the hospital.  So, she was ready to come get them and take them to dinner.  It was the first time that they met, but they immediately hit it off with Denise and her two adult children Seth and Emily.  I was so grateful!

The next morning, I took the kids to breakfast and we went out to the hospital to sit with Todd. He was doing better.  The fever was down, but they wanted to do a nasal wash to test for the flu along with a second CT with contrast of the right head/sinus along with the upper chest to get a better look. I knew they were calling in a head and neck surgeon and an infectious disease team, but I didn't think they would do much else.  I wanted to spend some "fun time" with the kids, so I took them to the Galleria Mall to look around and get dinner.  I texted Todd and checked on him several times to see if he wanted me to bring him food, but he said nothing about what happened while we were gone.  We walked into the room and noticed dry blood all over the front of his shirt and cotton gauze stuffed up his right nostril!

While we were gone, they sent in a Head and Neck Surgeon to take a look at the sinus fearing a fungal infection; and without any warning or pre-medication, he stuffed a large scissors-like tool up his right nostril to biopsy the sinus infection!  Todd said it was the most painful thing he has ever gone through! After the biopsy, he got up to go to the bathroom, when he had a gushing nosebleed!  The surgeon had to come back in and placing packing up his nostril to stop the bleeding. I felt so bad that I wasn't there; but he said there was nothing I could have done (except insist they give him something for the pain!).  The only good thing the surgeon did do was walk down the biopsy to the lab himself so we could get the results right away.

Todd was very congested after this and having some post-nasal drip after the procedure.  He had been pretty upset at the whole experience and had no appetite.  Before me and kids left to go back to the hotel, the results came back that the biopsy showed a fungal infection!  I really didn't fully understand what made a fungal infection so horrible or what they would have to do to treat it.  The team of doctors immediately wanted to schedule an MRI to get even a better look!  Our first worry was that they would want to surgically remove the infection, but with Todd's platelets so low, we doubted that this was a real option. We learned that a fungal infection can travel to other places like the brain and the eye where it can be extremely dangerous!  We left him in his room about an hour after visiting hours, because the kids were going home the next day and were anxious to spend more time with him.  I had also decided to check-out of our hotel room two nights early.  Since the kids were going home on Monday afternoon, I didn't want to waste resources staying two more nights by myself.  I could just pack a bag and plan on staying with Todd in his hospital room.  I knew this meant staying up all night packing up the hotel room!

I found out the following morning that they had taken him down for the MRI around 1:00 a.m. on Monday morning, November 7, 2016.  Life here for Todd was getting more complicated by the day. After a quick hotel breakfast, I started loading up the car with our things and we all headed out to the hospital to see Todd.  When we arrived, we learned that Todd not only had a fungal infection in his sinus but they also found nodules in his lungs, which are indicative of a fungal infection. They doctors said it isn't uncommon for the fungal infection to drop from the sinus into the lungs.

The doctors continued to treat him with anti fungal IV medication but they want to try giving him white blood cell transfusions to help fight the infections. Todd still has zero white cells to fight it.  They sent a representative in from the blood bank to discuss the process of donating white cells.  We learned that there is no storage bank for white cells since they have no shelf life; they have to be donated and given to him within 24 hours. Unlike transfusing red cells, they don't care about matching the donor cells to the patient, but it is a multi-day process for a donor to get screened and to have their white cells harvested  It is very hard to find donors for this reason and usually only family and close friends are willing to go through such a rigorous process.  I will be going as soon as possible to start the screening process! They really like multiple donors but since we are not local it just might be me only who can donate on a limited basis. We knew that we couldn't ask our own friends and family so far away in Ohio.  Instead, we would have to rely on what family we had here and if we could get the word out to people who had friends and family here that would be willing to help.

I had already planned for Todd's cousin Denise to take the kids to the airport on Monday afternoon, November 7, because Todd originally had out-patient appointments and bone marrow biopsy already scheduled during that time at the hospital. Even though those appointments were now cancelled and Todd had been admitted to the hospital, I didn't want to leave him after I wasn't there during the traumatic biopsy!  The kids, Denise, and her kids went downstairs and had a quick bite to eat.  Then I walked the kids out to the car to get their luggage.  It was hard to say goodbye, but the visit was so refreshing and we all felt better having been together (even though we were missing Abby). 

Large Flag hanging inside the Galleria Mall, along with a view of the ice skating rink and shops.

And just like our time together is gone...

Little did we realize how long it would take to fight this fungal infection.  It was just beginning.