Back From the Dead
When the answer to a medical mystery lies deep within the bones
“The dead man came out, his hands and feet wrapped with strips of linen, and a cloth around his face.” — John 11:44
“Long is the way and hard, that out of Hell leads up to light.” ―John Milton, Paradise Lost
Affliction
Lazarus had an inauspicious start to his life: As a puppy, he was rescued from a meth house in central Alabama during a police drug bust. Animal control often worked with a local veterinary clinic that pitied the poor creature and took him in.
He was emaciated, severely muscle wasted and unable to walk without assistance. Vets grade body condition score (BCS) on a scale of one to nine, with one being dangerously underweight and nine being morbidly obese. His BCS was listed as 1/9, and even that might have been generous.
His new adopted owners at the clinic were understandably worried and ran some baseline lab tests. On his complete blood count (CBC), Lazarus had an extraordinarily high white blood cell count. It was also increasing. 80,000 one day. 95,000 the next. Then it climbed past 100,000 without relenting. Normal is typically 5,000-15,000. Lazarus was also anemic, and his chemistry panel showed the enzymes creatine kinase and alkaline phosphatase were significantly elevated.
Their provisional diagnosis was myeloid leukemia, which carries a grave prognosis, and they planned to euthanize Lazarus. However, they wanted to give him one last Hail Mary chance and make sure there was absolutely nothing else treatable before making that final decision.
To investigate the possibility of leukemia they needed to collect a sample of bone marrow from Lazarus. This required inserting a large-bore stainless steel needle deep into his humerus just under the shoulder joint to suck out some of the thick, dark red, fatty tissue that forms our blood cells. This type of biopsy is notoriously painful in people, and the procedure is usually done while awake without sedation. Fortunately, in veterinary medicine we are a bit more humane and collect marrow under anesthesia.
His sample arrived at the Auburn University veterinary clinical pathology lab a few days later. I was in the middle of my first year of residency and excited to dig into this case as I was already finding my niche in hematopathology. While I hadn’t seen many bone marrow cases yet, I had my copy of Schalm’s Veterinary Hematology cracked open, ready to look up anything I needed.
When I peered down at the stained smear of marrow through the microscope eyepieces I was greeted by a kaleidoscopic burst of color with millions of cells of all different shapes and sizes packed together. Enormous deep blue megakaryocytes that form platelets, with their dozens of fused nuclei. An abundance of myeloid precursors that formed white blood cells like neutrophils and monocytes. The cells were numerous, but looked surprisingly…normal. Was this really leukemia? It looked more like the body was working over time to ramp up every line of defense it had against some intruder…
Something caught my eye as I panned around the slides.
A clear oval structure about 8-10 micrometers in size with icy blue internal staining within a neutrophil. Then another a few cells over. And another, and another. The more I looked, the more I found. There were was a raging infection in the marrow!
What was it, though? Too big to be bacteria, not any fungal organism I recognized. Flipping through textbooks, I found it: Hepatozoon americanum. PCR a few days later confirmed the diagnosis and species of the organism (more on that in a bit…)
We had our answer for Lazarus’ affliction; not cancer, but a parasite: Canine hepatozoonosis!
I called up the vets who had adopted Lazarus to give them what I thought was great news. They were also excited it was something treatable. We discussed the cocktail of powerful antibiotics and anti-parasitic drugs he would need to take for many weeks. When I hung up, I was glad to have given better than expected news, when so often our diagnoses as pathologists are terminal. My joy was abruptly punctured when my faculty mentor broke it to me that many of these dogs relapse in 2-6 months and succumb to the infection.
Discovery
Blood parasites have co-existed with animals and humans since time immemorial. Ancient threats like malaria have acted as both a scourge of humanity and as an evolutionary pressure towards traits like sickle cell red blood cells (those heterozygous for the gene are able to resist infection with Plasmodium falciparum).
The Hepatozoon genus of blood parasites includes over three hundred unique species. Until recently, only one was thought to infect dogs: Hepatozoon canis. This organism, carried by the common brown dog tick, was discovered on the Indian subcontinent in 1905 and originally called Leukocytozoon canis. It is found throughout Asia, Africa, the Middle East and Europe (hence the name “Old World” Hepatozoonosis). Most dogs with H. canis are mildly ill with non-specific waxing and waning signs.
Its life cycle is bizarre—while a tick-borne disease, unlike most vector borne pathogens that are transmitted when the tick bites through the skin of the host, Hepatozoonosis is contracted when dogs eat the infected tick (most often accidentally when grooming their fur or trying to remove the ticks). The infectious agent is rapidly flagged and engulfed by macrophages that guard the gastrointestinal tract, then taken to local lymph nodes which they hijack and use to spread throughout the body.
Old World Hepatozoonosis was not found in North America until the 1970s. Then, in the late 1990s, dogs in the southeastern United States were becoming severely ill with a mysterious new disease. In an ironic twist, Hepatozoon americanum—the parasite infecting Lazarus—was actually discovered at Auburn University, where I did my pathology training. After years of study, Auburn parasitologists and pathologists suspected Hepatozoonosis was making these dogs in Alabama, Mississippi and Louisiana sick, but it was radically different than the previously known entity. Unlike dogs with H. canis, these dogs were profoundly ill and presented to vets in pain and near the edge of death. The parasite was not carried by the brown dog tick vector, but rather the Gulf Coast tick (Amblyomma maculatum). There were other peculiar differences in morphology and genetics. It became clear this was a new beast, a novel species.
The disease caused by New World Hepatozoonosis truly is Hell. Parasitic cysts burrow within the muscles and cause contracture and difficulty walking. Osteoblasts in the long bones go wild and produce abundant amounts of new, disorganized bony tissue. These lesions are seen on bloodwork through the increases in the enzymes CK (muscle injury) and ALP (bone activity).
The disease caused by New World Hepatozoonosis truly is Hell.
Recovery
It’s a year and a half later. We’ve moved from the tiny lab in Horlein Hall to a giant new space in the center of the massive new teaching hospital they just finished building. I’m in the lab triaging a stack of cases and helping our new first year resident when the front desk calls and our lab manager yells back that there’s an owner up front that wants to see us.
“An OWNER?” I ask? Pathologists virtually never talk to clients.
I head down to the hospital lobby to see what’s going on. Waiting for me is a woman and a slightly chubby black Lab dog.
“Do you want to meet Lazarus?” she asks. He runs up and licks my hand. I immediately remember his diagnosis and I’m blown away by how different he looks from the photos they emailed me along with his case notes.
“Do you want to meet Lazarus?”
She says that she’s from the vet clinic that adopted him and they wanted to bring him by the vet school to show the people who diagnosed him his amazing turnaround. He’d recovered and become the clinic mascot, a symbol of hope. The hospital had brought lunch for the whole lab and we spent a few hours eating, catching up, and playing with Lazarus.
I took a photo with Lazarus outside the hospital to commemorate this rare moment. We almost never get to see the dramatic recovery from illness in person. To this day, I think about Lazarus and use his case as an example when teaching the next generation of veterinarians across the country. Besides the fascinating medical details of his case, he’s a perfect object lesson to never give up on a patient, even if they were born sickly in the most humble of origins in the middle of nowhere.
References
Baneth G, Allen K. Hepatozoonosis of Dogs and Cats. Vet Clin North Am Small Anim Pract. 2022 Nov;52(6):1341-1358.
Ewing SA, Panciera RJ. American canine hepatozoonosis. Clin Microbiol Rev. 2003 Oct;16(4):688-97.
Potter TM, Macintire DK. Hepatozoon americanum: an emerging disease in the south-central/southeastern United States. J Vet Emerg Crit Care. 2010 Feb;20(1):70-6.
Dr. Fish,
My Isaac, a Hurricane Katrina rescue, was diagnosed with H. canis on his 1st birthday and lived to 17 yrs and 20 days. He did relapse several times so we avoided his stressful situations such as boarding away from family.
I also rescued a chocolate lab in 2009 that had both H. canis and H. americanum, diagnosed at Auburn. He was the happiest boy and lived 12-13 years after his diagnosis.
A vicious disease but it is not the death sentence that it once was!
This warmed my heart. Thanks for sharing!