His Immune System Went Out of Whack. The Usual Treatment Didn’t Work. Why?

“Have you read this?” the 61-year-old man asked his newest doctor, Madan Jagasia, as they sat in an exam room in the cancer center at Vanderbilt University Medical Center in Nashville. The book, titled “Dying Well,” prompted a concerned look from the oncologist. You know we’re not there yet, he said he told the patient.

Jagasia had only recently taken over the patient’s care, but he knew the man had been through an awful 14 months. Just a few weeks before Christmas in 2016, the athletic and active lawyer discovered he had an aggressive leukemia. The patient first went through months of the brutal chemotherapy that makes up the first-line treatment, followed by a stem-cell transplant — in which progenitor blood cells from a donor are transfused into circulation to replace the patient’s diseased cells.

The treatment had been tough, but as he approached the next Christmas, the patient was finally feeling more like himself. He was still on immune-suppressing medications to keep his new immune system in check as it settled into his body. He had started a new job — one that would let him work at the slower pace he now needed. And he was getting his tennis game back into shape. Then, on Christmas Day, after the joyful orgy of presents with children and grandchildren and their traditional huge holiday breakfast, he started to feel unwell. He excused himself and hurried to the bathroom. It seemed that everything he’d ever consumed came out. The cramps twisted his insides in excruciating waves that left him breathless.

When the paroxysms finally stopped, the man felt exhausted — as if all his energy had left with the contents of his digestive system. He made it to his bed and wasn’t strong enough to get up again for hours. That evening he felt better, and a few days later, when it was time to go back to work, he thought he was ready.

But in a couple of days, he again had devastating diarrhea, which left him too weak to leave his house. Those episodes became a near daily occurrence. When he reported his symptoms to an oncologist on his cancer-treatment team, the doctor made the diagnosis of graft-versus-host disease (G.V.H.D.). That is, his transplanted immune system was attacking his body as if it were a foreign invader. The patient had a version of this weeks after his stem-cell transplant, when he developed a lumpy red rash: G.V.H.D. of the skin. His doctors upped the immune-suppressing medicines and started something called photopheresis, in which blood is routed out of the body, through a type of light that kills off the misdirected white cells, then back into circulation. The rash slowly faded.

G.V.H.D. was common, he was told back then. More than half of those who have the kind of stem-cell transplant he had will get it in some form. Once the rash disappeared, his doctors stopped the photopheresis and started lowering the dose of his immune-suppressing medications. This had to be done slowly so that the new cells and the old body had more time to get used to each other. And he’d done well, until that Christmas Day.

The form of G.V.H.D. he now had, located in his lower gastrointestinal tract, was far more serious than the type he had before, the oncologist told him. The doctor immediately increased the immune-suppressing medications. Usually that step provides relief within days. When it didn’t, additional medications were added. When that didn’t help, another medicine was added and titrated up.

Are you sure I have G.V.H.D.? he asked the oncologist. Over the first couple of weeks, he lost more than 10 pounds. The doctor ordered a biopsy of the lower GI tract, which was suggestive of mild G.V.H.D. but not definitive. That wasn’t uncommon with this disease. G.V.H.D. can elude testing; a diagnosis is usually made based on the patient’s story. He already had G.V.H.D. once, and the diarrhea started as he was being weaned from the immune-suppressing drugs. That clinical picture, even without the biopsy confirmation, made the G.V.H.D. diagnosis overwhelmingly likely.

And yet, why wasn’t the treatment working? The oncologist had no answer. After a few more weeks, the patient despaired. Am I dying? he asked the doctor, hoping to be reassured. But the doctor hesitantly acknowledged that he might be. The patient lost all confidence in him and told him so. Jagasia, the head of the cancer center, stepped in to oversee his care.

Jagasia was concerned that although G.V.H.D. was the most likely diagnosis, it might not be the right one. The patient had already been tested for the usual infections seen in immune-suppressed patients. So he looked for other possible causes of the patient’s diarrhea. He didn’t find any. The patient lost another 15 pounds. When he looked in the mirror, he hardly recognized himself. Jagasia arranged for the patient to start getting intravenous nutrition and began tapering one immune-suppressing medication in order to start another.

The patient’s son was in medical school in another part of the state and called home frequently. When his father finally told him how sick he was, his son got scared. His father was a minimizer. If he was saying this, things must be bad.

When he got off the phone, the young man immediately turned to the internet. He typed in “gastroenteritis after … stem-cell transplant.” The first results that came up referred to a paper in a medical journal, Clinical Infectious Diseases, published nearly a decade earlier that identified an unexpected culprit: norovirus.

Norovirus is one of the most common causes of gastroenteritis in the world. In the United States, it’s linked to an estimated 21 million cases of nausea and vomiting every year. Diarrhea can be present but is not typically as severe as other symptoms. In a normal host, the infection resolves on its own after 48 to 72 hours, thanks to the hard work of the immune system. Even so, norovirus was not a common cause of diarrhea in those who are immunosuppressed. But in the medical-journal paper, the first of its kind, 12 patients who had a stem-cell transplant and developed a persistent diarrheal illness were found to have norovirus. And of those 12, 11 were initially thought to have G.V.H.D. In most of those cases, it was only after the immune-suppressing medications were reduced that the patient’s own defenses could come to the rescue and vanquish the virus.

The son immediately sent the paper to his father. Had he been tested for norovirus? he asked. The patient wasn’t sure. He forwarded the journal article to Jagasia and asked if he’d had this test. He hadn’t. Jagasia was 99 percent certain that this was a wild-goose chase. He’d never seen norovirus in patients with compromised immune systems. Still, testing was easy.

When the test came back positive, Jagasia was stunned. He repeated the test. Positive again. He immediately started to taper the immune-suppressing medications. As the doses came down, the diarrhea slowed, and after a few weeks, it stopped completely. With the help of the IV nutrition, and a slowly improving appetite, the patient began to gain back the weight he lost. From the patient’s point of view, his son saved his life.

The patient had a good spring and summer. But in the fall of 2018, tests showed that his leukemia had returned. Despite aggressive treatment and intermittent improvement, the disease progressed. When I spoke with him in late February, he was in hospice. He had two goals. He wanted to make it to his daughter’s wedding in late March, and he wanted me to tell the story of how his son saved his life and gave him almost two more years with his family. He was so proud of his children.

Sadly, he didn’t make it to either goal. The patient died earlier this month.

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