Ethan Kilbourne is a now 18-year-old young man residing in Acworth, Georgia with his mother, Maria, and 14-year-old sister, Carmela. Unfortunately, at the age of 17, he was one of the many individuals who contracted a deadly E. coli O157:H7 illness after consuming what he believed to be a healthy and nourishing food option: romaine lettuce. Ethan consumed the lettuce on April 8, 2018, as part of his dinner during a family outing to the Texas Roadhouse restaurant located at 2475 Barrett Creek Pkwy NW, Marietta, Georgia.

Ethan Kilbourne

Symptom onset

Ethan’s symptoms did not become obvious to him until Friday, April 13, 2018. However, by that date, the teenager described his urine as dark, and he admitted to having diarrhea that was so bad he could no longer control it. On the 13^th, Ethan called his mother to let her know he was not feeling well and, by the time Maria arrived home, he was suffering from severe stomach cramps and bloody stools. Rightfully alarmed at what her son was experiencing, Maria quickly took Ethan to urgent care.

Children’s Healthcare of Atlanta – Urgent Care

On April 13, 2018, Maria brought Ethan to the urgent care at Children’s Healthcare of Atlanta (CHOA), where Lesley O. Wilkerson, MD evaluated him for abdominal pain and bloody stools. Ethan reported the sudden onset of symptoms earlier that day, which consisted of 3-4 episodes of bloody stools and abdominal pain that was focal to the mid to lower abdomen. He had no distinct urinary tract symptoms, but he complained of discomfort in the lower abdomen while urinating. Dr. Wilkerson found Ethan’s exam unremarkable. She told him he probably had gastroenteritis and requested that he return a stool sample to the clinic as soon as he could collect one. He left the clinic with a stool collection kit he could use in privacy, and his mom returned his specimen to the clinic later that day.

Home but not better…

Maria recalls that her son Ethan’s condition only worsened after his initial visit to urgent care:

Over the course of the night into the morning, Ethan’s condition dramatically worsened. He was screaming in pain. I had given him Tylenol in the morning, as advised by the doctor at CHOA but it wasn’t working. When I drove to CHOA to drop off his stool sample, Ethan called me to tell me he was in unbearable pain. The nurse I was speaking with said to go ahead and take him to the emergency room. On the way to the emergency room, I had to pull over because Ethan was howling in pain and thought he might have to go to the bathroom on the way there. He didn’t think he’d be able to make it there without having diarrhea.

Wellstar Kennestone Hospital

At around 2 PM on April 14, 2018, Ethan and Maria arrived at Wellstar Kennestone Hospital in Marietta, Georgia, where William R. Smith Jr., MD evaluated him in the emergency department. In triage, Ethan described the onset and progression of his diarrhea illness, explaining that he had already been seen at urgent care the day before but had gotten worse. He had already had five bloody and mucousy stools that day alone. He stated he had also been retaining fluid. He answered questions about possible exposures, but he could not think of anyone else who was sick, and he had not traveled or been taking antibiotics recently. His abdominal pain varied in intensity, with levels as high as 10/10 at home, but somewhat better by the time he arrived in the ER. His exam was significant for diffuse abdominal tenderness, and the doctor thought he looked ill. There was no rebound tenderness or guarding to suggest underlying inflammation, but his bowel tones sounded hyperactive.

While Ethan was under observation in the ER, he tolerated oral fluids without difficulty. Dr. Smith sent urine and blood to the lab for analysis and asked him to give a stool sample as soon as he could. The stool specimen provided to urgent care the day before was still pending results. Ethan’s complete blood count and metabolic panel were largely unremarkable, although his total bilirubin was elevated at 3.0. He was able to produce a urine sample, and a dipstick test was significant for 1+ blood; however, his urine did not look infected microscopically. Ethan was kept under observation for about three hours, after which the doctor deemed him stable enough to go home to self-treat with fluids and rest. Dr. Smith noted that Ethan was able to “jump without pain or apparent discomfort.”

Dr. Smith discussed Ethan’s lab results with him and his mom, including his concerns that his symptoms might have a bacterial etiology; however, he found it reassuring that “… there were no lab or physical findings were consistent with Shiga + etiology.” Dr. Smith assigned Ethan a “final diagnosis” of gastroenteritis. He talked about home management of his symptoms and advised Ethan to follow-up with his pediatrician, Dr. Holladay, but to return to the ER if his symptoms got worse. Ethan was able to give a stool sample before leaving the hospital.

Continued suffering at home…

Ethan continued to suffer immensely over the next few days. Maria recalls learning the cause of his painful symptoms:

Ethan was in horrible pain all day on Sunday. I gave him alternating medications to try and help with the pain, but his condition was progressively becoming worse. I received a phone call from Wellstar Kennestone that the test results came back, and Ethan had E. coli O157. I was told that he should not need additional hospitalization, and that we could treat this at home.

Confirmation of Shiga-like toxin-producing E. coli(STEC) and E. coliO157

On Sunday, April 15, 2018, the Kennestone Hospital laboratory reported a critical value to the ER that Ethan’s stool sample submitted in on the 14^th was positive for Shiga-like toxin-producing E. coli, as well as E. coli O157, by GI Multiplex PCR testing. It was negative for the other enteric pathogens on the panel. Kerry Parfitt, RN received the result at 11:06 AM. The hospital notified the health authorities of Ethan’s positive STEC infection.

Decision to return to the hospital…

Ethan’s mom recalls that it was not long before they knew he needed to receive medical attention at the hospital:

… over the course of Sunday night to Monday morning, Ethan’s pain intensified. He was passing pure blood in his stools and was in excruciating pain that would not stop.

I spoke to a nurse at his pediatrician’s office to let them know that his condition was not good, his level of pain was extremely high, and that he had uncontrollable bloody diarrhea. I asked her to speak withthe doctor regarding his condition, because this did not seem like the normal level of pain manageable with home treatment. She said she would call back. Ethan was begging me to take him back to the emergency room, he was in absolute, complete, non-stop pain.

I didn’t hear back from the nurse, so I called the doctor’s office back twice. When she finally returned my call, she said she spoke with the doctor, and if he was in that much pain, we should take him to the emergency room.

Wellstar Kennestone Hospital

It was past 6 PM on Monday, April 16, 2018 when Ethan arrived back at Wellstar Kennestone Hospital. The triage nurse performed his first assessment and reviewed his history of urgent care and ER visits over the prior few days. His mom recounted the phone calls to and from the ER and doctor’s office, when they learned that Ethan had E. coliin his stool, but no medications were needed. However, since he had not improved and was even getting worse, they decided to come back to the hospital. Ethan stated there had not been any blood in his stool that day, but he was having abdominal pain that was quite severe and not responding to over-the-counter analgesics. The nurse observed that his eyes appeared “a little jaundiced,” and he was now complaining of lower back pain as well.

ER attending Michael B. Dinerman, MD evaluated Ethan just before 7 PM, who told the doctor he was having the “worst abdominal pain of [his] life.” While under observation and awaiting the doctor’s evaluation, Ethan was placed under contact isolation, given his STEC infection. He received intravenous fluids with morphine for his pain, and blood was sent to the lab for analysis. A complete blood count revealed a normal white blood cell count of 8.2. Ethan was not anemic (hemoglobin 14.9, hematocrit 42%), and his platelet count was in normal range at 195K. A CRP was mildly elevated at 1.3.[1]

CT evidence of colitis

At 7:58 PM, Ethan was taken to radiology for a CT scan of his abdomen and pelvis. Anjani Naidu, MD performed the contrast-enhanced exam, during which he identified mild wall thickening of the transverse and descending colon, compatible with colitis. Dr. Naidu also noted findings suggestive of possible SMA syndrome[2], as well as a small to moderate amount of free fluid in Ethan’s pelvis. After receiving the results of the CT scan, Dr. Dinerman conferred with the hospitalist service, who agreed to admit Ethan to the pediatric ward for hydration and further pain control.

Admission to hospital – Shiga-toxin associated E. coliO157 infectious colitis

At 9:41 PM, pediatric hospitalist Carrie Stinson, MD formally admitted Ethan for his diagnosis of Shiga-toxin associated E. coli O157 infectious colitis. She concurred with the exam done in the ER and reassured Ethan and his mom that, so far, his labs were “reassuring against HUS.” She was uncertain as the cause for his elevated total bilirubin (2.9), as his liver enzymes were normal. She noted the suspicion for SMA syndrome mentioned in the CT results, but she thought that diagnosis was unlikely since Ethan was not actively vomiting.

The nursing staff noted that Ethan was “initially pain free” when he arrived on the ward. However, after he ambulated to bathroom just before midnight, his abdominal cramping resumed. He became very anxious, frightened that his pain was going return to the level that had brought him back to the ER. Dr. Stinson ordered a dose of Levsin[3]to deal with the cramping, with little effect.

Hospital Day 2 – intractable abdominal pain

Ethan had a rough night, with a resurgence of pain that required several doses of morphine to get him comfortable, although the doctors were trying to avoid giving him narcotics. He finally drifted off to sleep around 6 AM.

At around 10 AM on April 17, 2018, Kimberly Crosland, MD came in for the hospitalist service and found Ethan afebrile but still having profuse, bloody diarrhea. She noted that his severe abdominal pain was unrelieved by Levsin, and even the morphine stopped being helpful when it began to wear off. Ethan reported pain levels up to 8/10 on a 1-10 pain scale by the time his next morphine dose was due. Dr. Crosland continued his morphine and added Toradol for additional pain control. Ethan was unable to tolerate oral fluids, requiring maintenance IV fluids, with only a few ice chips by mouth. His bloody diarrhea continued through the day.

Hospital Day 3-4 – continued pain

On April 18, 2018, Ethan awoke at 5:30 AM to abdominal pain at a continued high level of intensity, despite being dosed with both Toradol and morphine during the night. Pediatric hospitalist Dipika Sharma, MD evaluated him around 8 AM, finding him afebrile with stable vital signs. His morning labs were reassuring, including a normal white count and platelets in normal range at 173K. Ethan was not anemic, despite his continued bloody diarrhea. As they day wore on, Ethan began to tolerate more orally but still required IV fluids. He was also beginning to tolerate a few bland foods.

Dr. Sharma returned to check on Ethan’s progress during morning rounds on April 19. The nursing staff reported the bloody diarrhea had not ceased, with two instances occurring overnight and one in the morning. Ethan had not required any morphine overnight, with Toradol successfully controlling his pain. Nevertheless, Ethan stated that, although he was feeling better, he had not slept well because of the cramping. His morning labs were stable. Dr. Sharma discontinued Ethan’s morphine. He wrote orders for Toradol to be used for severe pain only, with oral Tylenol as his main source of pain relief.

Hospital Day 5 – slowly improving

On April 20, 2018, Langdon S. Dimaggio, MD evaluated Ethan during morning  rounds. He observed that Ethan’s stools were no longer bloody. They were also less frequent, and he was not vomiting. He was able to eat a little at each meal and was increasing his oral intake of fluids. His pain was controlled with Levsin and Toradol; Ethan expressed that Tylenol alone was insufficient and left him feeling more nauseous. Dr. Dimaggio observed that Ethan’s labs were mostly normal, with his total bilirubin and CRP still mildly elevated if slowly downtrending. Ethan was doing better at tolerating oral fluids, but he still required an IV infusion to maintain his hydration and deliver parenteral pain medication.

Hospital Day 6 – discharged home

Dr. Dimaggio was back to see Ethan in the morning on April 21, 2018, finding him improved over the day before. He was still having watery stools but without blood. His CBC and metabolic panel were stable. Ethan had been able to ambulate and shower independently since he saw him last, which he stated helped him feel better. Ethan expressed a desire for some non-hospital food, which Dr. Dimaggio thought was a good sign. His pain was now down to manageable levels on oral medications, and he was drinking enough to discontinue his IV after being trialed that morning with an oral challenge of 6-8 ounces of fluid. Ethan was a little worried about going home, fearing the pain would return the same as when he arrived. Dr. Dimaggio reassured him that he had demonstrated significant improvement and was expected to do well at home with adequate dosing of Motrin and Tylenol. Although Ethan was still having mild abdominal discomfort and still had some diarrhea, Dr. Dimaggio deemed him stable enough to leave the hospital. He discharged him later that afternoon with instructions to follow-up with Dr. Holladay in a few days. His discharge diagnosis was “diarrhea and abdominal pain due to E. col iO157:H7 infectious colitis.”

Wellstar Medical Group – Kenmar Pediatrics

On April 26, 2018 at 9:30 AM, Ethan went to see his pediatrician Candace B. Holladay, MD at Kenmar Pediatrics. Dr. Holladay observed that Ethan had been discharged from the hospital on Saturday, April 21^st, and she reviewed the details of his illness and hospitalization. Since he left the hospital, he reported being relatively inactive and had only been consuming bland foods and liquids. He reported having formed bowel movements, but they still contained blood. He was “urinating well,” but “applesauce color.” At the time of this visit, Ethan had not been taking pain medications for two days and said that his abdomen felt better, but only if he lay flat. He was sleeping a lot—12 hours—and admitted to eating grilled cheese, pizza and grits. He was drinking ginger ale and water.

Dr. Holladay was alarmed at Ethan’s exam. She was concerned to hear that he had suddenly gained 14 pounds in the five days leading up to this visit—his knees and ankles were swollen with 2+ pitting edema. His blood pressure was normal, but a urine sample was abnormal, showing a large amount of protein (3+) and blood. Dr. Holladay ordered stat blood work to include a comprehensive metabolic panel and complete blood count. She allowed Maria and Ethan to go home, but she cautioned them to remain on standby pending notification of his lab results.

Diagnosis Hemolytic Uremic Syndrome

When Dr. Holladay received the results of Ethan’s labs, they contained a number of significant abnormalities, including a very low platelet count of 60,000, severe anemia, and a serum creatinine elevated to 1.6 mg/dL. She diagnosed Ethan with hemolytic uremic syndrome and contacted his mom to take him to the hospital immediately.

Maria recalls:

I had gone back to the office to work that week and informed my boss that I may have to take Ethan back to the doctor, depending on the phone call I received. As I was packing up to leave, Dr. Holladay called back. She had called a kidney doctor at CHOA at Egleston hospital in Atlanta, for Ethan to be directly admitted. I had to arrange for care for my daughter and was able to board my two dogs at the vet before heading over to the hospital with Ethan.

Children’s Healthcare of Atlanta at Egleston Hospital – admitted for HUS

At around 8 PM on April 26, 2018, pediatric residents Laura Wang, MD and Rachel Stewart, MD received Ethan at the Children’s Healthcare of Atlanta at Egleston Hospital, bypassing the emergency department as a direct admission from Dr. Holladay’s pediatric clinic.Drs. Wang and Stewart evaluated Ethan under the supervision of attending Sabina S. Kennedy, MD. The doctors reviewed the onset and progression of Ethan’s diarrhea illness, including his admission for STEC a week earlier, “… and now with lab findings consistent with HUS (anemia, thrombocytopenia, elevated creatinine).”

The doctors noted that Ethan had gained 3kg since he was discharged on the 21^stand was mildly edematous. They planned to monitor his kidney function, anemia, blood pressures and urine output carefully. Ethan reported that his abdominal pain had resolved, and his stools had since normalized. He appetite was slowly increasing though he continued to be very tired. His mom told the doctors that that over the last few days, Ethan had worsening swelling of his feet and he was having difficulty wearing his shoes. His baseline weight was 145 pounds and he was 161 pounds at the pediatrician that day. “The pediatrician thought Ethan looked tired and sick today so checked labs which were ‘abnormal’ per mom, so she was told to come to Egleston for direct admission.” Ethan also had a headache for the prior 2 days, for which he took Motrin at home. He reported “normal” urine output. He denied having any chest pain, abdominal pain, shortness of breath, or difficulty breathing.

Maria told the doctors that they had been in contact with the health department regarding Ethan’s possible exposures to E. ColiO157:H7. “Per mom, they were at Texas Roadhouse on 4/8 were they all ate a house salad. On 4/12 (the day he developed the symptoms), he ate a rotisserie chicken and mashed potatoes from Kroger and was the only one to eat these.” On exam, the doctors noted that Ethan had normal blood pressure; however, he had a pinpoint petechial red rash on his legs, abdomen, and chest.

Turning to Ethan’s current lab results, the doctors noted an increased creatinine (1.3 mg/dL), decreased hemoglobin (8 g/dL), decreased platelets (61K), elevated LDH (655)[4], “… which is consistent with AKI in the setting of HUS triggered by STEC infection.” There were occasional schistocytes[5]noted on his peripheral blood smear. They determined that Ethan did not require a blood transfusion and held off giving him diuretics for the time being. Because his urinary output was normal and he was clinically stable, the doctors were able to treat him with supportive care and careful monitoring of his labs. As noted in the pediatric clinic, Ethan’s urinalysis was again significant for 3+ blood and 100 mg/dL of protein. The labs planned for the morning included a repeat CBC, plus an LDH, haptoglobin, and C3/C4 analysis. Ethan was admitted under contact precautions secondary to his STEC infection.

Maria recalls the fear generated by this second hospital admission:

Upon admission, we found out that he had been diagnosed with Hemolytic Uremic Syndrome – HUS – as a result of the initial E. coliinfection. The doctor explained the seriousness of this diagnosis to me, and that HUS is a kidney failure. He was placed in another isolation room on the Nephrology floor. His entire body and face were swollen. The potential for it to be deadly was overwhelmingly frightening.

CHOA Day 2-3

On April 27, 2018, Ethan’s morning labs returned results showing his complement protein were within normal results. His white count remained in normal range. His hemolytic anemic worsened, with a hemoglobin and hematocrit of 7.5 and 22.5%, but his platelets rose slightly to 69K. His BUN and creatinine were stable at 27 and 1.3. His LDH fell slightly to 539. His haptoglobin[6]was low at <14. Ethan felt well and had no new complaints on the 27^th. His edema improved without the use of diuretics, and he did not require a blood transfusion.

Rouba Garro, MD and Jasmine Weiss, MD came in for pediatric nephrology on April 28, 2018. Ethan’s morning labs showed stable or slightly improving anemia (hemoglobin 7.6, hematocrit 22.2%), and a BUN and creatinine of 23 and 1.2. The doctors talked with Maria, who reported that Ethan had been afebrile since he was discharged from the hospital on the 21^stand she had not noticed any new rashes. Other than his significant leg swelling and pitting edema, his main complaint had been a headache for the 2 days before he came back to the hospital, and this resolved with Motrin at home. She reiterated that he appeared to exhibit normal urinary output. On exam, the doctors noted that Ethan’s lower extremity edema had resolved, and he no longer had a petechial rash on his chest or extremities. They deemed Ethan sufficiently stable for discharge home that afternoon, with a plan to follow his labs as an outpatient and to visit the nephrology clinic in about two weeks.

On April 30, 2018, Ethan’s BUN and creatinine had returned to normal range (15 and 1.0). He remained significantly anemic with a hemoglobin and hematocrit of 8.6 and 26.3%, but this reflected improvement as well. His platelets had returned to normal range at 202K.

CHOA Outpatient Nephrology

On May 14, 2018, Ethan presented to the CHOA outpatient nephrology clinic for a visit with Sabina Kennedy, MD, in follow-up of his Shiga toxin HUS. Dr. Kennedy noted that his follow-up labsshowed improved creatinine and normal platelets. His energy and color had both improved. He had no new complaints that day, and his blood pressure was in normal range. His urine was negative for protein and blood. Dr. Kennedy reassured Ethan and Maria that his acute kidney injury was relatively mild, and he never exhibited any oliguria or hypertension. She discussed his excellent prognosis and did not think he needed any additional lab studies that day. She gave Ethan the okay to resume a regular diet without salt restrictions, and she told him he could resume exercising and working out. Because he had still been anemic at his last blood draw, she recommended anover the counter iron supplement. Dr. Kennedy encouraged Ethan to stay well hydrated and wanted him to come back for repeat labs in August.

Ethan returned to see Dr. Kennedy on August 13, 2018. He stated his energy had normalized and he had no new complaints that day. His blood pressure was normal, and his urinalysis showed no protein or blood. His last creatinine was 0.9 mg/dL, which Dr. Kennedy indicated was normal for his height and age. She released Ethan to routine pediatric follow-up and asked him to return for another follow-up in a year.

Aftermath

Ethan’s battle with E. coli and HUS was a frightening time for both him and his family. His mother vividly recalls everything her son endured and the impact such a severe illness had on his day-to-day life and the repercussions the illness had on his family:

We are so fortunate for him to have survived this illness. There were days when he was crying and screaming, in excruciating pain, with abdominal cramps and constant internal spasms, with uncontrollable bloody diarrhea, that I feared he wouldn’t be able to make it through. His whole life was disrupted – we had to take him out of classes and enroll him months later once he was strong enough to go back. He was completely incapacitated by this illness and weakened for a long time after. It took a substantial physical and emotional toll on Ethan.

I am a divorced mother of two children, with two dogs. Because their father lives 4 hours away, and no other family is nearby, I had to arrange for my daughter to stay with various friends throughout Ethan’s illness and both hospitalizations. I was worried that I wasn’t there to help her with school and all the issues that arise for a young teenaged girl. I also had no one to help take care of our dogs so I was forced to board both dogs at our veterinarian’s office, which was unexpected and costly.

It is hard to articulate just how horribly stressful, overwhelming, frightening, emotional, and traumatic this illness was. It all happened so fast, and Ethan’s condition deteriorated so quickly and so intensely, that I seriously thought he would not live through it. If he wasn’t a very healthy and physically fit teenager, I truly do not believe he would have survived this illness.

It has been exceptionally difficult for me to even write this, because it brings back so many painful memories of this time period. Our lives were thrown completely out of control due to not knowing the outcome of how Ethan would make it through an illness that intensified and progressed so rapidly. We were lucky and are so thankful to have had excellent doctors and nursing staff during both of his hospitalizations.

The causal link between Ethan Kilbourne’s E. col i O157 infection and romaine lettuce from Texas Roadhouse is clear. On April 8, 2018 Ethan consumed a filet mignon with salad from Texas Roadhouse located in Marietta, Georgia.

Ethan began to experience symptoms consistent with Shiga toxin-producing E. coli (STEC) on April 12, 2018. An exposure on April 8 is consistent with an STEC incubation period that averages 3 to 4 days but can range from 1 to 10 days. A stool specimen collected on April 13, 2018 was positive forShiga toxin-producing E. coli (STEC) at Children’s Health of Atlanta Urgent Care located in Marietta, Georgia. The Georgia Public Health Lab further tested Ethan’s specimen and found his specimen to be genetically linked to the Yuma, Arizona romaine E. colioutbreak strain (PFGE pattern EXHX01.0047/ EXHA26.0626).

Several other confirmed STEC cases ate at the same Texas Roadhouse and around the same time as Ethan. Therefore, public health officials visited the implicated Texas Roadhouse location and found several concerns at the restaurant, including that multiple employees were sick around the time when Ethan dined at the location. The Georgia Department of Public Health concluded that this restaurant was the source of the STEC infections.

Given Ethan’s confirmed infection with E. coli O157, his exposure to romaine lettuce within the average STEC incubation period and at an implicated outbreak-associated location, and the genetic evidence connecting his infection to the outbreak, Ethan was considered as a confirmed case in the Yuma, Arizona romaine E. coli outbreak (Outbreak ID 1804MLEXH-1) by the Georgia Department of Public Health.

_________________________

[1]          Reference ranges for this lab: WBC 3.5-10.5K, hemoglobin 13.5-17.5 g/L, hematocrit 39-50%, platelets 150-450K, total bilirubin 0.0-1.2 mg/dL, BUN 5-18 mg/dL, creatinine 0.7-1.2 mg/dL, CRP <0.5 mg/dL, LDH

[2]          Superior mesenteric artery syndrome (SMAS) is a digestive condition that occurs when the duodenum (the first part of the small intestine) is compressed between two arteries (the aorta and the superior mesenteric artery). This compression causes partial or complete blockage of the duodenum. Van Horne N, Jackson JP. Superior Mesenteric Artery Syndrome. [Updated 2018 Oct 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK482209/

[3]          Hyoscyamine (i.e., Bentyl, Levsin) is a natural plant alkaloid derivative and anticholinergic that is used to treat mild to moderate nausea, motion sickness, hyperactive bladder and allergic rhinitis.It is used to provide symptomatic relief of spasms caused by various lower abdominal and bladder disorders including peptic ulcers, irritable bowel syndrome, diverticulitis, and pancreatitis.https://livertox.nih.gov/Hyoscyamine.htm

[4]          Reference ranges for this lab: WBC 4.5-13.5, hemoglobin 13.0-16.0 g/dL, hematocrit 36-50%, platelets 150-450K, BUN 5-22 mg/dL, creatinine 0.3-1.0 mg/dL, LDH 2.9-5.0 mg/dL, haptoglobin 30-200 mg/dL

[5]          The hallmark of hemolytic uremic syndrome in the peripheral smear is the presence of schistocytes. These consist of fragmented, deformed, irregular, or helmet-shaped RBCs. They reflect the partial destruction of red blood cells (RBCs) that occurs as they traverse vessels partially occluded by platelet and hyaline microthrombi. The peripheral smear may also contain giant platelets. This is due to the reduced platelet survival time resulting from the peripheral consumption/destruction. A consumptive coagulopathy is typically not present. Nayer, Ali, and Luis M. Ortega. “Journal of Nephropathology.” Journal of nephropathology 3.1 (2014).

[6]          The hemolytic-uremic syndrome (HUS) is defined by the association of hemolytic anemia (low haptoglobin levels, high lactate dehydrogenase levels, and schistocytes), thrombocytopenia, and acute renal failure. Olivia Boyer and Patrick Niaudet, “Hemolytic Uremic Syndrome: New Developments in Pathogenesis and Treatment,” International Journal of Nephrology, vol. 2011, Article ID 908407, 10 pages, 2011. doi:10.4061/2011/908407

Lawrence J. O’Connor is a 70-year-old gentleman residing in Beresford, South Dakota with his wife Ruth. Lawrence and Ruth were visiting his daughter in Phoenix, Arizona for a few weeks when they decided to go out for dinner. On Friday, March 23, 2018, the two went to dinner at Red Lobster located at 7921 W. Bell Rd. in Peoria, Arizona 85382. Lawrence chose a Caesar salad made with romaine lettuce, and his wife and a regular salad.

Lawrence and Ruth in February 2018

Symptom Onset

Over the next 24-48 hours after Lawrence and his wife dined at Red Lobster, he began to get sick. He first had stomaching cramping and diarrhea on Monday, March 26, 2018. The diarrhea continued to get worse and he noticed there was blood in it on Tuesday. By the following day, there was so much blood he could no longer pass it off as hemorrhoids or something insignificant, and he decided to seek medical care.

Banner Thunderbird Medical Center

Just before 9 PM on Wednesday, March 28, 2018, Lawrence presented to Banner Thunderbird Medical Center, where Jody Boyer, PA evaluated him in the emergency department under the supervision of Kristen Niedner, MD. In triage, Lawrence described have abdominal pain and diarrhea since Monday, March 26, which had become bloody the morning of the 28^th. He had experienced three bloody stools since then and decided to seek medical attention in the ER. He described his abdominal pain as non-focal, and his stool were previously watery. He had vomited once. Lawrence described that it was the bright red blood in his diarrhea that caught his attention and caused him great alarm, leading to the ER visit. He answered questions about possible exposures to suspect food or others who were sick, and he stated he had not been out of the country, had not taken any recent antibiotics, and had not eaten any food he thought was bad. He indicated he had not been around others with similar symptoms.

On exam, PA Boyer found Lawrence afebrile with unremarkable vital signs. She confirmed diffuse abdominal pain and stool positive for occult blood by guaiac testing. His abdomen was soft and non-distended, without guarding or rebound tenderness. The PA sent blood and urine samples to the lab, which returned results showing an elevated white blood cell count of 15.4.[1]

CT scan – mild acute colitis

At 11:50 PM, radiologist Raul Galvez-Trevino, MD performed a contrast-enhanced CT scan of Lawrence’s abdomen and pelvis, during which he identified mild acute colitis involving the ascending and transverse colon, suspicious for either an infectious or inflammatory etiology. He also observed possible mild right pyelitis (kidney inflammation) that he thought warranted further investigation. The PA conferred with the attending physician, who concurred with a clinical impression of “acute diffuse abdominal pain,” “acute rectal bleeding,” “acute ascending and transverse colon colitis,” and “possible mild right pyelitis,” noting his co-morbidities of hypertension history, coronary artery disease, arthritis, and hyperlipidemia.

While he was under observation in the ER, Lawrence was started on intravenous fluids and IV antibiotics (Levaquin 750 mg and metronidazole 500 mg), and a recheck of his anemia by CBC revealed a stable blood count. The hospitalist service was consulted and the decision was made to admit Lawrence for observation, at least overnight.

Arun Pillai, MD came in for an urgent gastroenterology consultation while Lawrence was still in the ER and reviewed the CT results with radiology. Dr. Pillai thought that Lawrence had a lower gastrointestinal bleed related to his right-sided colitis. He was not sure of the cause but was most suspicious for an infectious etiology and less likely an inflammatory etiology. He opined that ischemia was unlikely, based on the distribution of colitis seen on CT. Dr. Pillai observed that Lawrence’s initial stool results were back, showing negative for toxigenic C. difficile.

Admission to hospital

It was after midnight on March 29, 2018 by the time Sanjay Kulkarni, MD formally admitted Lawrence to the hospital for abdominal pain and rectal bleeding. He noted that Lawrence had a medical history that was significant for coronary artery disease (“status post 4-vessel CABG”), hypertension, and hyperlipidemia. He repeated his history and physical exam, and Lawrence reiterated that he started to have diarrhea 2 to 3 days prior to admission. “This was with almost every time he ate.” Lawrence also reported having fevers and chills at home. He stated he took a full-strength aspirin tablet (325 mg) every day but was not on any other blood thinners. He reported his abdominal pain level as severe, or about 8/10 on a 1-10 pain scale. Lawrence reported a previous colonoscopy 8 years earlier in South Dakota and was told it was normal. Dr. Kulkarni noted that Lawrence had not been tachycardic or hypotensive in the ER. He admitted Lawrence on telemetry observation and continued his IV antibiotics.

Hospital Day 2 – discharged home

On March 30, 2018, hospitalist Karen Alonzo, MD evaluated Lawrence for discharge from the hospital. She reviewed his blood work and deemed him clinically stable and appropriate for continued self-care at home. She provided a written prescription to continue taking Levaquin and Flagyl in oral form to complete a ten-day course, as well as Zofran for nausea and Percocet for pain. She advised him to follow-up with his PCP and gastroenterology as an outpatient. His stool studies were still pending at the time he was discharged home.

Confirmation of stool-positive Shiga toxin 2

After Lawrence had already been discharged from the hospital, at 8:48 PM the Banner Hospital laboratory reported a critical value that his stool had tested positive for Shiga toxin 2. The lab report carried the warning: “Positive Shiga-toxin results are most commonly due to Shiga-toxin producing E. coli (O157 or non O157 STEC) which may cause enterohemorrhagic disease and Hemolytic Uremic Syndrome (HUS). Antimicrobial therapy is not required unless the corresponding stool culture is also positive for Shigella.”[2]

On March 31, 2018, the Banner Hospital Laboratory reported that Lawrence’s stool culture was negative for growth of Salmonella, Shigella, and Campylobacter.

Home but not better…

Lawrence recalls: “[The hospital] gave me pills to take and sent me home on Friday. I still had bloody diarrhea. On the Monday after Easter, I got up and passed out enough to fall. My wife called the ambulance and they came and checked me out and I passed out again. They then took me to a different hospital as for what was wrong a different one was better.”

Phoenix Fire Department

On Tuesday, April 2, 2018 around 8 AM, EMS responded to a call from Lawrence’s family that he had an episode of dizziness and almost fainted.  Upon their arrival at the family residence, the first responders found Lawrence sitting, alert, and oriented. He stated that he was not having any chest pain, difficulty breathing, or loss of consciousness, and he had not become diaphoretic before the near-syncopal event. They transported him via ALS ambulance transport to the hospital.

Honor Health – Deer Valley Hospital

Lawrence arrived at Deer Valley Hospital around 9 AM on April 2, 2018, where Michael Saam Karbasi, MD evaluated him in the emergency department. Dr. Karbasi observed that Lawrence had just been discharged from Thunderbird on Friday, March 29, where he had been kept overnight for colitis and rectal bleeding. Lawrence reported that he began feeling dizzy while in the shower the night of the 30^th before falling down that morning. The near-syncopal episode had been witnessed by his wife.

According to the EMS report, Lawrence’s initial blood pressure at the family residence was 66/42, but after a 500 cc bolus of IV fluids, it improved to 82/46. Lawrence had his hospital records with him from Thunderbird, with the CT scan result that showed mild acute colitis. He stated that he had been taking his antibiotics as prescribed since he was discharged home three days earlier, and his diarrhea had started to improve; however, he continued to have persistent rectal bleeding, although the amount was small and his stool was beginning to return to normal color. Lawrence also mentioned that he had a poor appetite and was not hydrating well since going home, although he had not had any more fevers, and no sore throat, cough, nausea, vomiting, urinary complaints, abdominal pain, shortness of breath, or chest pain. He complained of no other symptoms at that time.

Dr. Karbasi restarted Lawrence on IV fluids and send blood to the lab, which returned results showing he still had significant leukocytosis and now exhibited severe anemia and thrombocytopenia, as well as acute renal failure (WBC 25.9, hemoglobin 9.6, platelet count 95K, BUN 94, serum creatinine 7.5). A 12 lead EKG was obtained that showed “sinus bradycardia with 1st degree AV block, rate 59, no ST or T wave elevations or depressions.”

Consultation advises hospital admission

At 11:47 AM, Dr. Karbasi consulted with Shannan Murphy, MD of hospitalist service, who agreed to admit Lawrence to the hospital telemetry unit. She, in turn, requested a nephrology consultation and additional lab tests for clotting abnormalities, as well as insertion of a Foley catheter into his bladder so his fluid balance could be carefully monitored. Dr. Karbasi also consulted with infectious disease about Lawrence’s lab results, after which he immediately stopped Lawrence’s antibiotics, concerned about the risk for hemolytic uremic syndrome, given his anemia, thrombocytopenia, and renal failure. He also requested a stat CT scan.

CT shows colitis and other abnormalities

Tamim Sultani, MD performed an unenhanced CT scan of Lawrence’s abdomen and pelvis, during which he identified extensive colon wall thickening, for which the main differential considerations included infectious/inflammatory colitis or ischemic colitis. In addition, he observed bilateral kidney stones but particularly in the right renal pelvis, as well as gallstones and cirrhosis[3] of Lawrence’s liver. He also observed a small amount of ascites and a small right pleural effusion.

Nephrology Consultation – Possible HUS

Around 2 PM, Guneet Mumick, MD came in for a nephrology consultation and noted that Lawrence’s stool had tested positive for Shiga toxin 2. He reviewed his abnormal renal function labs and told Lawrence and his wife that his acute renal failure was probably secondary to hemolytic uremic syndrome. He told him about the positive Shiga toxin result according to the Banner/Thunderbird records. Lawrence also exhibited low blood sodium, metabolic acidosis, and lower extremity swelling. They discussed the implications of HUS, as well as the possibility of acute tubular necrosis (ATN) from low blood pressure versus acute interstitial nephritis (AIN) from having taken Levaquin. He continued Lawrence’s intravenous fluids, adding oral bicarbonate to his medications. Finally, he discussed that he was going to need hemodialysis as soon as the next day, if his abnormal renal function did not turn around on his lab results. Dr. Mumick added a peripheral blood smear and a haptoglobin level to his blood tests, as well as checking an ADAMTS13 test. They discussed the use of Eculizumab (Soliris) for infectious HUS if there was central nervous system involvement, but he wanted to hold off for now. He planned to monitor his fluid intake and output carefully via IV management and Foley catheter urine measurements

Infectious Disease Consultation

At 4:55 PM, Walid Almut, MD came in for infectious disease at the request of Dr. Murphy. She requested that he consult regarding Lawrence’s “Shiga toxin positive E. coli HUS.” Dr. Almut observed that a stool culture had not been finalized at Thunderbird that confirmed E. coli, although he suspected it was the likely diagnosis. He noted that Lawrence was clinically worse after being given Levaquin and Flagyl, “… which is also more suggestive of Shiga toxin E. coli strain.” Dr. Almut saw that Lawrence had tested negative for toxigenic C. difficile. He emphasized that all antibiotics should be avoided entirely, and Lawrence’s treatment should consist of supportive care only, with IV fluids and albumin. Lawrence was currently afebrile and his blood pressure was improved after receiving additional IV fluid boluses. Dr. Almut requested blood tests for CRP and procalcitonin.

Hematology Consultation – no convincing evidence for HUS

Mazen Khattab MD came in for a hematology consultation at 5:47 PM regarding Lawrence’s anemia and thrombocytopenia. Lawrence reported that he was still having rectal bleeding, and that morning he had experienced a syncopal episode and was found to have anemia and thrombocytopenia with renal failure. Dr. Khattab observed that Lawrence’s hemoglobin that day was low at 9.6, as were his platelets at 85K.

Dr. Khattab reviewed a chest x-ray taken at 4 PM, comparing it to a Nuclear Lung Scan to rule out a pulmonary embolism. Radiologist Jimmy Saade, MD’s chest x-ray impression was that Lawrence had COPD, with “blunting of both costophrenic angles, consistent with small volume pleural effusions versus pleural thickening.” On the Nuclear Medicine V/P scan, there were no observable abnormal matched or mismatched ventilation or perfusion defects. Barry Sadegi, MD observed a symmetric, bilateral distribution of radiopharmaceutical medium on both the perfusion and ventilation images, indicating a negative test result for pulmonary arterial embolism.

Finally, Dr. Khattab personally reviewed Lawrence’s peripheral blood smear. There were rare schistocytes^[4], “… but not convincing for MAHA[5] (HUS).” He noted that his LDH was elevated (>300), but his haptoglobin was normal. He commented: The anemia and thrombocytopenia could be from bleeding and acute inflammation and not necessarily from MAHA, especially given the lack of convincing significant schistocytosis on peripheral blood smear. He wanted to monitor Lawrence’s LDH and haptoglobin^[6] and peripheral blood smear over the next 24-48 hours before making a final determination.

Hospital Day 2 – Hemodialysis No. 1

On April 3, 2018, Dr. Murphy came in for the hospitalist service during morning rounds and observed that Lawrence had become oliguric^[7], with a urinary output of less than 200 cc overnight. His hemoglobin had fallen to 8.8, down from 9.6 gm/dL the day before. His white count was still markedly elevated at 24.5. His BUN and creatinine were 94 and 7.5. A urine culture was pending. Dr. Murphy consulted with nephrology, who made the decision to start Lawrence on hemodialysis that day. Dr. Murphy put in an order for the insertion of a hemodialysis catheter, with the first HD treatment to be initiated afterward.

Hematologist Dr. Khattab came in at 9 AM, and Lawrence told him his rectal bleeding was slowing down and his diarrhea was improving. Dr. Khattab reviewed his labs, noting that his LDH was going down and his haptoglobin was normal. He commented in his chart note:

This argues against ongoing hemolysis. The anemia and thrombocytopenia could be from bleeding and acute inflammation and not necessarily from MAHA, especially given the lack of convincing significant schistocytosis on peripheral blood smear. In fact, platelets are improved today. I will monitor LDH and haptoglobin. At this point, I would monitor conservatively. No convincing evidence of MAHA at this point to justify plasma exchange. Patient is going for HD per Dr. Mumick. Discussed with Dr. Murphy and Dr. Mumick.

Guarav Patel, MD performed the insertion of a right internal jugular temporary hemodialysis catheter later that morning, which was done under fluoroscopy with a right neck entry and selection of a 21 gauge, 5 Fr. dual-lumen catheter. Both lumens were easily aspirated and flushed, and a subsequent chest x-ray confirmed the correct placement with the tip in the superior vena cava. Immediately after HD catheter insertion, Miguel Gonzalez, RN initiated HD under the supervision and direction of the nephrology service, Lixian Zou, MD. Lawrence tolerated the procedure well and was transported back to his room in stable condition after the procedure. His next hemodialysis was scheduled for the 5^th.

HD catheter insertion

Lawrence was visited by the various specialists on the 3^rd and no other changes were made to his care plan. He remained afebrile with stable blood pressures and was beginning to feel better.

Hospital Day 3 – Hemodialysis No. 2 – anuria and altered mental status

On April 4, 2018, Lawrence continued to have diarrhea, although it was no longer bloody. He was now producing almost no urine and was having swelling in both lower extremities. Doppler studies failed to demonstrate any blood clots in the deep veins of his legs. Dr. Katthad continued to trend Lawrence’s lab results, noting a continued decline in his LDH level and a return of his platelets to normal range, and his haptoglobin and peripheral smear were unremarkable. However, Dr. Zou observed that he was effectively anuric with only a 100 ml urinary output in 24 hours, despite of a 5-liter positive fluid balance (3820 input, 2420 output, accounting for fluid removal in dialysis as well as urinary output). His renal function remained markedly abnormal, with a BUN and creatinine of 71 and 7.9.

Dr. Zou discussed doing a renal biopsy to assist with diagnosing the cause for his renal failure, and Lawrence agreed to the procedure and it was scheduled for the 5^th. His urine culture was not growing any bacteria thus far. Although hemodialysis had been planned to skip a day and resume on the 5^th, Dr. Zou ordered a second session that morning given his worsening renal status.

Dr. Murphy came in for the hospitalist service around midday and was concerned to hear that Lawrence was having hallucinations. He reported seeing things in his room like a hair net and seeing water on the floor when there was none. His blood pressure was doing better and was currently 113/58. He continued to receive albumin in his IV fluids to combat a tendency for hypotension. Dr. Murphy discussed Lawrence’s altered mental status with him and his wife at the bedside, with a plan to consult psychiatry. She was less concerned that his white count was still elevated at 22.9 as he remained afebrile. He was tolerating a renal diet.

Hospital Day 4 – Hemodialysis No. 3 – Renal biopsy

On April 5, 2018, Lawrence’s renal function was no better, with only 120 ml of urinary output in 24 hours, although his serum creatinine was improved at 6.8. What little urine he was producing was significant for a large amount of protein, bilirubin, and leukocyte esterase. His white count remained elevated at 20.3. His liver enzymes were slightly elevated over the prior few days, but a viral hepatitis screen was negative. Another hemodialysis session was implemented that afternoon.

Dr. Murphy came in for the hospitalist service and noted that Lawrence had continued to exhibit confusion during the night. He was better at the time of her visit, but the nurses remarked he had been “quite agitated” overnight. He was alert and oriented to Dr. Murphy’s exam but wanted to know when he could leave the hospital. She ordered an atypical antipsychotic drug (risperdone[8]) for his agitation while a psychiatry consultation was pending.

In the early afternoon, William Romano, MD took Lawrence for a CT guided left-renal cortical core biopsy, which was satisfactorily performed using conscious sedation. The biopsy samples were sent to surgical pathology for analysis. Later in the evening, Kimberly M. Nelson, PA came in for a psychiatry consultation regarding Lawrence’s altered mental status, with confusion and hallucinations. He was doing better that day, but she continued him on the medication started by Dr. Murphy, adding Ambien to be used as needed if he had trouble sleeping. She planned to visit Lawrence daily and remained available for consultation.

Hospital Day 5

On April 6, 2018, Dr. Khattab came in for hematology and reviewed Lawrence’s morning labs, noting that his LDH continued to go down and his haptoglobin was normal. “This argues against ongoing hemolysis.” He again opined that Lawrence’s anemia and thrombocytopenia could be from bleeding and acute inflammation and not necessarily from MAHA, especially given the lack of convincing significant schistocytosis on his peripheral blood smear. His platelets continued to be in normal range. His hemoglobin was slowly worsening since the 4^th (8.3à7.9), but his white count had been slowly improving during that time (22.9à20.8).

Dr. Mumick came in for nephrology during the afternoon and observed that Lawrence was still oliguric, but he deferred hemodialysis that day. He considered Lawrence’s hemoglobin “relatively stable,” but his BUN and creatinine remained significantly abnormal at 32 and 5.5, although that was improved from the 5^th (49 and 6.8). Lawrence’s renal biopsy results were still pending, as were his results for ADAMTS13^[9] testing.

Hospital Day 6-8 – Hemodialysis No. 4 and 5

On April 7, 2018, Lawrence underwent his fourth hemodialysis treatment. He was still oliguric, but Dr. Mumick approved the removal of his Foley catheter, as he was clinically stable. Dr. Mumick gave Lawrence a break from hemodialysis on April 8 and resumed it on the 9^th, potentially planning the next session for the 11^th. On April 9, 2018, Lawrence’s white count was almost down to normal range, and his anemia remained stable.

Hospital Day 9-10 – Renal biopsy shows post-infectious glomerulonephritis

On April 10, 2018, surgical pathologist Ekaterina Castano, MD called and discussed Lawrence’s renal biopsy results with nephrologist Sachin N. Desai, MD and give him on preliminary report, explaining the findings were suggestive of post-infectious glomerulonephritis. There was no indication of acute tubular necrosis. Dr. Desai reviewed Lawrence’s labs the next morning of April 11, 2018, which showed a worsening of his creatinine level, but his urinary output had begun to increase. He had some lower extremity swelling suggestive of fluid overload, but he had no chest pain or shortness of breath. Dr. Desai did not think Lawrence needed hemodialysis that day.

Hospital Day 11-12 – Discharged. home

On April 12, 2018, Dr. Desai came back to see Lawrence in the afternoon and was happy to hear that his urinary output continued to increase. This was by subjective reporting, as Lawrence’s Foley catheter had been removed. His white count was in normal range and his anemia was stable, if still significant. His BUN and creatinine had improved to 37 and 2.4 off dialysis. Dr. Desai ordered the removal of his hemodialysis catheter.

Hospitalist Lawrence Chua, MD came in to evaluate Lawrence for discharge home on April 13, 2018. He reviewed each day of his hospitalization for the record and noted that Lawrence had received five hemodialysis treatments. His episodes of confusion had not recurred, and psychiatry continued the antipsychotic medication as needed after an initial consult. A brain CT showed no acute intracranial disease. Physical therapy and occupational therapy worked with Lawrence during the last few days of his hospitalization, working to mobilize him and improve his stamina for a safe discharge to home self-care with only minor assistance from his family. Lawrence was discharged from the hospital that afternoon with the discharge diagnoses of “acute renal failure secondary to acute tubular necrosis and post-infectious glomerulonephritis—no evidence of acute interstitial nephritis,” “bloody diarrhea with stool positive for Shiga toxin 2,” “anemia,” “colitis,” “thrombocytopenia—improved,” “hyponatremia—improving,” “metabolic acidosis—improving,” “lower extremity swelling,” “hypotension—better with albumin and NS,” and “elevated liver function.”

Return to Deer Valley Hospital – possible pulmonary embolism

Over the next few days,  Lawrence experienced some episodes of shortness of breath when he was up and about, as well as awakening at night feeling uncomfortable in his upper chest. On April 15, 2018, he returned to Deer Valley Hospital in the early afternoon, where Jennifer Prosser, DO admitted him from the emergency department after a chest CT revealed he had small bilateral pleural effusions. She thought this was consistent with compressive atelectasis and/or pneumonia. He had a small right kidney stone, minimal ascites, as well as gallstones noted on imaging. Lawrence reported he still had leg swelling, but venous duplex monitoring of his lower extremities ruled out a deep vein thrombosis. His labs showed a normal white count and stable anemia, and his renal function showed continued improvement since he was discharged on the 13^th.

Dr. Prosser ordered a nuclear medicine lung V/Q scan to rule out a pulmonary embolism. Interventional radiologist Barry Sadegi, MD performed the exam and identified a “large triple-matched defect of the right lower lobe, with intermediate probability for pulmonary arterial embolism.” Dr. Prosser requested a pulmonary consultation.

Hospital Day 2

On April 16, 2018, Cristian Jiveau, MD came in for the pulmonary consultation and reviewed the imaging from the night before. He identified a number of concerns, including the CT chest that suggested right lung consolidation vs. atelectasis, as well as the V/Q scan revealing a likely pulmonary embolism. Dr. Jiveau started Lawrence on IV antibiotic therapy with Unasyn and advised that he be up and ambulating while he was hospitalized. He ordered Mucomyst[10] for renal protection prior to getting pulmonary CTA imaging to investigate the possible embolism further. Dr. Jiveau consulted with nephrology, who thought that Lawrence needed to be diuresed, but they would hold that for 24 hours after the IV contrast needed for the pulmonary CTA to avoid further renal injury.

Dr. Mumick came in for nephrology and reviewed the renal lab results done on Lawrence’s admission, noting an improvement of his serum creatinine to 1.4 that day. He observed that he had been put on a heparin drip to minimize a deep vein thrombosis and that he was slated for a CTA the next day to definitively diagnose or rule out a pulmonary embolism. He agreed with aggressive diuresis after the CTA and agreed with the Mucomyst premedication.

Hospital Day 3-4 – CTA rules out pulmonary embolism

On April 17, 2018, Lawrence underwent a pulmonary CT angiogram, which was negative for a pulmonary embolism. David Porvin, DO came in for pulmonary and noted that Lawrence had improved shortness of breath and he was being successfully diuresed after the CTA. His doctors were able to stop his heparin drip and changed it to three times daily injections for DVT prophylaxis. Lawrence continued to do well overnight, and he was initially planned to be discharged from the hospital on April 18, 2018. Ronald Allen Charles, MD evaluated him and reviewed his hospital course. After consulting with nephrology, the decision was made to keep Lawrence an extra night for continued diuresis.

Hospital Day 5 – going home

On April 19, 2018, Lawrence was doing well and had no recurrent of dyspnea. His doctors felt that his clinical presentation that led to his current admission was likely the result of fluid overload that was residual from his prolonged hospitalization for E. coli infection, acute renal failure, and hemodialysis. He was released that afternoon to outpatient follow-up. Dr. Charles gave him a prescription for a diuretic to take at home.

Home and slowly improving…

Charles reflects on his hospitalization and going home to South Dakota:

I had 5 dialysis treatments because my kidneys were not working. My sister from South Dakota had flown down and was staying at a nearby hotel. My kidneys started working again with lots of prayers from family near and far. At that point they let me go back to my daughter’s home in Phoenix for a few weeks. My wife’s sister flew down from South Dakota and helped to drive us home.

Sanford Health – Beresford Clinic

May 14, 2018, Charles presented to Sanford Health – Beresford Clinic – in Sioux Falls, South Dakota, where Judith Nelson, APRN saw him in follow-up of his hospitalization for “bloody diarrhea after eating Casear salad at a fast food restaurant.” She noted that Lawrence had just returned home to Beresford the week before. On exam, she found his lungs were clear, and his lab work that day revealed still-abnormal renal function, with a BUN and creatinine of 23 and 1.40. She made no changes to his medications (Bumex for diuresis, and hydralazine for blood pressure) and asked him to return in three months for a recheck. Lawrence returned to see NP Nelson on July 20, 2018 for unrelated blood pressure issues and chronic knee pain.

Avera Medical Group Nephrology – diagnosis CKD Stage 3

On August 15, 2018, Lawrence presented to Avera Medical Group Nephrology, where Arvin Santos, MD saw him in follow-up of acute renal failure. Dr. Santos observed that Lawrence did not have a known history of chronic kidney disease until being hospitalized the previous April with enteritis/colitis needing short term dialysis in Arizona, although a review of his records revealed microscopic hematuria in 2012. He had a longstanding history of hypertension but no diabetes.

Dr. Santos diagnosed Lawrence with acute renal failure with hematuria and proteinuria, which he thought was likely chronic kidney disease stage 3 (CKD-3). He thought that Lawrence’s serum creatinine was stable since his admission and that his current value could be his new baseline. He explained the importance of hypertension, hyperlipidemia, and blood sugar control to avoid worsening kidney disease. He advised Lawrence to avoid NSAIDs, since they could also cause kidney failure. Lawrence admitted to taking a lot of NSAIDs in the past. Dr. Santos requested lab tests to include blood testing for autoimmune disorders, as well as a renal ultrasound.

Lawrence underwent a bilateral renal ultrasound on August 26, 2018, which revealed kidney stones (calculi) that were non-obstructing, and a follow-up CT scan was ordered. On August 21, the CT scan was performed by Jonah Luzier, MD, during which he observed an increase in the size of his bilateral renal calculi. The extrarenal right renal pelvis remained mildly dilated at 17 mm which was decreased from 21 mm by comparison with prior imaging.

On September 6, 2018, Lawrence returned to see Dr. Santos and discussed that his clinical presentation laboratory analyses were consistent with a diagnosis of chronic kidney disease, stage 3 (CKD-3).^[11] His serum creatinine was stable at 1.3, which he reiterated was likely his baseline. They discussed his renal CT, showing dilation of right pelvis, as well as possible hydronephrosis. Dr. Santos noted that Lawrence had seen Matthew Witte, MD at Urology Specialists Clinic in the past, who would re-consult. Dr. Santos explained the importance of hypertension, hyperlipidemia, and blood sugar control to avoid worsening kidney disease. He also explained the importance of avoiding NSAIDs since this could also cause kidney failure.

Dr. Santos advised a renal stone diet, which included but was not limited to low salt, low animal protein, low oxalate, and normal calcium dietary intake. He advised him to increase his oral fluids to achieve a urine output goal of greater than 2 liters in 24 hours. Finally, Dr. Santos addressed Lawrence’s history of gout and the need to keep his uric acid under 7 to avoid worsening renal function.

Urology Specialists Clinic

On October 22, 2018, Lawrence presented to Urology Specialists Clinic, where Dennis Thum, MD saw him in consultation for his “significant right-sided stone burden noted on CT.” He reported no current pain from his kidney stones. Dr. Thum ordered a urine culture and discussed doing a right ureteroscopy laser lithotripsy to break up the stones. After discussing the risks and benefits, Lawrence agreed to the procedure. This was done on November 9, 2018 at USC Ambulatory Services Center. He continued follow-up with Dr. Thum in December.

Aftermath

Charles reflects on his E. coli infection and how he is doing now:

It was not fun running to the bathroom every little while, and this still continues. I had to wear diapers for quite some time which is humiliating. I don’t remember a lot of what happened as they gave me a lot of pain medications. When I started dialysis I became very depressed and gave the RN’s a bad time and thought I was done for. My family had left me in the hospital and I thought I was going to be there for a long time or forever. I was very unhappy and felt like my life might be over.

Most everyone I knows was in South Dakota so I was not able to spend time with them until I was well enough to return home. I probably wasn’t the best of company myself, you tend to feel sorry for yourself in these situations, wondering how it will turn out. I am lucky my friends came to see me and support me. My sister and sister in law both flew down to Arizona were great support for both me and for my wife. My sister cheered me up and my sister in law helped us pack up to drive back home. Most of my friends are in South Dakota so I had a lot of people calling and texting me their love and support.

The doctors told me what could happen to me, to have me prepared for the worst and the best that could happen as a result of my kidney damage from contracting e coli. I am glad the worst has not happened, but I worry about the future as a result of what happened. I am hoping to get better as time goes by.

It has slowed me down a lot. When traveling anywhere, I have to be aware of where a restroom could be constantly. I have to urinate frequently because of one of the pills I now have to take to get rid of excess fluids. I have not been able to golf , I lost a lot of weight while in the hospital and it has been hard to regain my strength back.

I now have a kidney Dr. Santos,  in South Dakota and was tested this past week and said I have 52-53% kidneys working at present. I have to be careful not to harm them anymore.

 

Lawrence looking gaunt on March 6, 2019

The causal link between Lawrence O’Conner’s E. coli O157 infection and the romaine lettuce that he consumed at Red Lobster is clear. Lawrence consumed contaminated romaine lettuce in a Caesar Salad from Red Lobster located in Peoria, Arizona on March 23, 2018.

Lawrence began to experience symptoms consistent with E. coli infection on March 26, 2018. An exposure on March 23 is consistent with an incubation period that averages 3 to 4 days for Shiga toxin-producing E. coli (STEC). A stool specimen collected on March 29, 2018 tested positive for STEC O157 and Shiga toxin at Banner Thunderbird Medical Center in Glendale, Arizona. This specimen was sent to the Arizona Department of Health Services, as Lawrence was spending time in Arizona that winter, where further genetic testing determined that Lawrence’s E. coli infection was a genetic match to the Yuma, Arizona romaine E. coli outbreak strain (PFGE pattern EXHX01.0047/ EXHA26.0626).

Given Lawrence’s infection with STEC O157, his exposure to romaine lettuce within the average STEC incubation period, and his illness during the peak of the multistate outbreak associated with Yuma, Arizona romaine lettuce, Lawrence was identified as a confirmed case in the Yuma, Arizona romaine E. coli outbreak (Outbreak ID: 1804MLEXH-1) by the South Dakota Department of Health.

____________________________________________________

[1]           Reference ranges for this lab: WBC 4.0-11.0K, Hgb 13.5-17.0 g/dL, hematocrit 40-53%, platelets 130-450K, BUN 5-20 mg/dL, serum creatinine 0.5-1.30 mg/dL, AST 14-59 U/L, ALT 11-66 U/L, total bilirubin 0.0-1.3 mg/dL, CRP 0.0-9.9 mg/dL, ESR 0-20 mm/hr

[2]           It is unclear in the medical record whether Lawrence was notified of the positive Shiga toxin 2 result.

[3]                Cirrhosis is a chronic disease of the liver characterized by scarring of the liver with loss of normal hepatic architecture and areas of ineffective regeneration. Clinical symptoms result from loss of functioning liver cells and increased resistance to blood flow through the liver (portal hypertension). Venes, Donald. Taber’s Cyclopedic Medical Dictionary (Taber’s Cyclopedic Medical Dictionary (Thumb Index Version)) (Page 494). F.A. Davis Company. Kindle Edition.

[4]           The hallmark of hemolytic uremic syndrome in the peripheral smear is the presence of schistocytes. These consist of fragmented, deformed, irregular, or helmet-shaped RBCs. They reflect the partial destruction of red blood cells (RBCs) that occurs as they traverse vessels partially occluded by platelet and hyaline microthrombi. The peripheral smear may also contain giant platelets. This is due to the reduced platelet survival time resulting from the peripheral consumption/destruction. A consumptive coagulopathy is typically not present. Nayer, Ali, and Luis M. Ortega. “Journal of Nephropathology.” Journal of nephropathology 3.1 (2014).

[5]           Microangiopathic hemolytic anemia

[6]           The hemolytic-uremic syndrome (HUS) is defined by the association of hemolytic anemia (low haptoglobin levels, high lactate dehydrogenase levels, and schistocytes), thrombocytopenia, and acute renal failure. Olivia Boyer and Patrick Niaudet, “Hemolytic Uremic Syndrome: New Developments in Pathogenesis and Treatment,” International Journal of Nephrology, vol. 2011, Article ID 908407, 10 pages, 2011. doi:10.4061/2011/908407

[7]           Oliguria is defined as a urine output that is less than 1 mL/kg/h in infants, less than 0.5 mL/kg/h in children, and less than 400 mL daily in adults. It is one of the clinical hallmarks of renal failure and has been used as a criterion for diagnosing and staging acute kidney injury (AKI), previously referred to as acute renal failure. https://emedicine.medscape.com/article/983156-overview

[8]           Risperdone is an atypical antipsychotic sometimes used to treat “ICU delirium.” While the pathophysiology of delirium is still not entirely understood, there is certainly evidence to support the hypothesis of a final common pathway of an ongoing hyperdopaminergic and hypocholinergic state perhaps triggered by oxidative stress and associated with excitotoxicity. Trzepacz PT. Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry. 2000;5(2):132–148. [PubMed]

[9]           In nearly all patients, aHUS can be distinguished from TTP on the basis of an ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) enzyme activity measurement. It is essential that aHUS and TTP be differentiated quickly, as they require markedly divergent treatments. The standard treatment for TTP is plasma exchange, a therapy that has no role for patients with a diagnosis of aHUS established by ADAMTS13 activity levels. http://www.hematologyandoncology.net/files/2013/02/ho1012_sup171.pdf

[10]         Mucomyst (NAC) is the brand name for acetylcysteine, a medication ordinarily used to treat acetaminophen overdose. It is also used to loosen thick pulmonary mucus secretions, such as is seen in cystic fibrosis or COPD, as well as to prevent contrast-induced nephropathy (CIN). Although the exact mechanism responsible for the protective action of NAC from renal function deterioration remains unclear, the antioxidant and vasodilatory properties of NAC have been suggested as the main mechanisms. Jo, Sang-Ho. “N-acetylcysteine for Prevention of Contrast-Induced Nephropathy: A Narrative Review” Korean circulation journal vol. 41,12 (2011): 695-702.

[11]         A person with stage 3 chronic kidney disease (CKD) has moderate kidney damage. This stage is broken up into two: a decrease in glomerular filtration rate (GFR) for Stage 3A is 45-59 mL/min and a decrease in GFR for Stage 3B is 30-44 mL/min. As kidney function declines waste products can build up in the blood causing a condition known as “uremia.” In stage 3 a person is more likely to develop complications of kidney disease such as high blood pressure, anemia (a shortage of red blood cells) and/or early bone disease. Reference: https://www.davita.com/kidney-disease/overview/stages-of-kidney-disease/stage-3-of-chronic-kidney-disease/e/4749

Louise Fraser is a 66-year-old woman who lives in Flemington, New Jersey with her husband David. She and David have two adult children, Brian and Rebecca, who are in their thirties. Louise works in property management for Punia and Marx, Inc. On March 20, 2018, Louise purchased and consumed a Fuji Apple Chicken Salad at Panera Restaurant in Raritan, New Jersey. She had no way of knowing that the salad was contaminated by the potentially deadly fecal pathogen, E. coliO157:H7 and she was soon to become violently ill as a result.

Louise Fraser

Symptom onset

After leaving the restaurant, Louise went about her day and did not immediately feel sick. However, over the next few days she knew there was something seriously wrong with her. She first experienced loose stools on March 23, 2018, which progressed to full-blown diarrhea on the 24^th. Over the next 24 hours, she developed severe stomach cramping, nausea, vomiting, headache, body aches, and a fever of 101.3ºF. When her diarrhea turned bloody, she knew she had to seek medical attention.

Hunterdon Medical Center

On Sunday, March 25, 2018 at around 8 PM, Louise presented to Hunterdon Medical Center, where Tracey Keegan, APN evaluated her in the emergency department. In triage, Louise described having a stomach ache since the previous Friday, which she blamed on eating fried foods. But she got worse and worse over the weekend, and that morning she had nausea and vomiting, with one episode so violent she became incontinent of her diarrhea stool. That was when she noticed the blood in her stool. While changing into a gown in the ER, the nursing staff noticed that Louise was wearing a maxi pad to spare her clothing from the diarrhea, which was covered in bloody stool. She reported having taken Excedrin for her fever, and she was currently experiencing constant lower abdominal cramping.

On exam, Louise did not have a fever and her exam was largely unremarkable. She was started on intravenous fluids to correct her dehydration and blood was sent to the lab for analysis. When the results began to filter in, her white count was in normal range but exhibited a predominance of neutrophils. Her kidney function was currently unremarkable, but her liver enzymes were marginally elevated (ALT 65, AST 69), and her potassium was low. A urinalysis was negative for infection. Stool was also sent to the lab for analysis, with the results pending. Her coagulation profile (INR/PT) was in normal range.

Colitis on CT

Louise underwent an IV-contrast-enhanced CT of her abdomen and pelvis, which revealed a diffusely edematous-appearing right colon, with a small amount free fluid adjacent to her liver. The radiologist also noted mild sigmoid diverticulosis, as well as a 13 mm “sharply demarcated smoothly marginated pancreatic cystic lesion.” The latter finding was not considered significant to Louise’s acute clinical presentation but the radiologist thought this should be reassessed by MRI. The nurse practitioner conferred with the hospitalist attending, who decided to admit Louise to the hospital for colitis. While awaiting a bed, she was made more comfortable in the ER with the administration of morphine for her pain and Zofran for nausea. Her doctors initially suspected Louise might have spontaneous bacterial peritonitis and started her on intravenous antibiotics (ciprofloxacin and Flagyl) while she was still in the ER.

Hospital Day 1 – Shiga toxin E. coli (STEC) confirmed

It was after midnight on March 26, 2018 by the time Mimi Mak, MD formally admitted Louise to the hospitalist service. She was most suspicious that Louise had infectious colitis and put her on a clear liquid diet, continuing the antibiotic therapy with ciprofloxacin and Flagyl. A recheck of Louise’s potassium showed it had already rebounded, and the rest of her electrolytes were also stable. Dr. Mak requested a gastroenterology consultation for Louise’s colitis.

Howard Garson, MD came in for the gastroenterology consultation at the request of Dr. Mak, agreeing with her assessment that Louise likely had infectious colitis. A preliminary test for toxigenic C. difficile was negative, and there were fecal leukocytes^[1], but the other stool studies were pending. Dr. Garson wanted to do a colonoscopy the following morning for further evaluation, and he wanted an MRI done to look at the pancreatic cyst. Later that evening, the laboratory reported a critical value to the floor that Louise’s stool was positive for Shiga toxin E. coli (STEC). The laboratory reported Louise’s Shiga toxin E. coliresult to the health authorities. With a new diagnosis of STEC, Dr. Mak discontinued Louise’s Flagyl, but she continued the ciprofloxacin.

Hospital Day 2-4

On March 27, 2018, Dr. Mak came in for the hospitalist service, and Louise reported that she was still feeling very sick. Over the next 24 hours, her abdominal pain improved and she described it as more like “gas pain” than the sharper cramping she was having before. She still had bloody diarrhea, but the quantity was diminishing.

Radiologist Lara Branche, MD and Andrea Lyons, MD took Louise for a contrast-enhanced MRI of her abdomen on March 28, 2018. They thought the pancreatic cystic lesion looked benign but should be followed up in about six months. They continued to observe “abnormal-appearing” bowel loops, consistent with enterocolitis. The radiologists also identified a moderate amount of ascites^[2]in Louise’s abdomen.

The next 24 hours brought more discomfort, abdominal distension, and bloating, and Louise complained of increased gassiness. Her diarrhea was improving, and she was no longer nauseated. Louise’s bloating was so prominent, Dr. Mak suspected an ileus^[3], but the MRI and x-rays showed no acute findings besides the colitis. She treated Louise with simethicone for the gas and provided IV morphine for pain.

Louise recalls how painful her abdomen was:

Similar to childbirth, the exact nature of my pain is a blur. But I definitely remember indicating the pain was generally 8-10 on a scale of 1-10. I also remember feeling so bad that I did not want the TV on, could not talk with anyone on the phone (my husband took care of communication with family) and wanting to keep my eyes closed for at least the first 4-5 days. Additionally, I did not want to eat. I was limited to a liquid diet for quite some time and had no interest in broth as I had vomited after having chicken soup a few hours before going to the hospital. I had a few servings of my favorite food, ice cream, but then could not even manage to eat that. I hardly ate anything for about 8-10 days.

Initially the pain I experienced required morphine, then Motrin, and finally other over the counter pain relievers. My doctors were very concerned about my kidneys and kept pushing fluids to prevent my kidneys from shutting down and eliminating the need for dialysis. They were also constantly monitoring my blood tests that resulted in serious concern regarding white cells, platelets, creatinine, and red cells.

During my stay I underwent many tests including daily blood tests, CAT Scan, Ultrasound, and MRI. Halfway through my stay an ultrasound indicated the need for the very painful paracentesis procedure during which using a needle they drained 2.5 cups of fluid from my abdomen. This unexpected procedure when I was about to be released made me actually fear going home. Because of the fluid retention and limited activity, I was very uncomfortable and wanted to be certain I would not need to return after being released. I had heard that another victim was released after a week only to be readmitted

Hospital Day 5

On March 30, 2018, Louise continued to be miserable with distension, bloating, and gas. Her diarrhea continued. Her labs showed an elevation of her white blood cell count to 18.9, and she developed acute blood loss anemia, with a hemoglobin of 9.9. Dr. Mak was concerned about Louise’s symptoms and repeated an ultrasound that showed her ascites was getting worse. Louise was taken to interventional radiology for a paracentesis to remove some of the fluid. The radiologist removed 600 mL of ascitic fluid and sent it to the lab for analysis. The lab reported that the fluid contained white blood cells and blood, and a culture was set up of the fluid. Louise felt more comfortable after the paracentesis, but it was transient.

Hospital Day 6 – HUS

On April 1, 2018, Louise’s lab results exhibited a number of significant abnormalities, including a drop in her platelets to 23K, and her hemoglobin and hematocrit to 8 and 23.1%. Her white count was still elevated if improved at 15.6K. Her liver function was normalizing. Her BUN was 22 and creatinine 0.98. Dr. Mak requested a hematology consultation.

Hematologist Kenneth Blankenstein, MD came in for the consultation and reviewed Louise’s peripheral blood smear himself, identifying “a left-shifted^[4]myeloid morphology” as well as occasional schistocytes. Dr. Blankenstein commented in his chart note:

Certainly in the face of Shigella [sic] toxin, one has to be concerned about [Shiga] toxin-induced HUS (hemolytic uremic syndrome). This is less likely with a normal renal function. However, her creatinine has been slowly rising and sometimes with this entity it takes time for the renal insufficiency to develop.

I do see some signs of what looks like a microangiopathy with schistocytes and therefore, will need to rule out TTP (thrombotic thrombocytopenic purpura). My plan is to order an LDH which should be elevated in both of these entities and a reticulocyte count as well. I will also get a haptoglobin and an ADAMTS13 to rule out TTP. DIC (disseminated intravascular coagulation) looks like it has been ruled out so I don’t think this is the cause. The other possibility is that it could be drug-related. The antibiotics were stopped today. My plan is to see what her numbers are tomorrow, get other tests, she may need further intervention possibly with plasmapheresis if we think this is a true microangiopathic process

Infectious disease consultation – antibiotics discontinued

With hemolytic uremic syndrome added to the list of Louise’s potential diagnoses, an Joseph Gugliotta MD came in for an infectious disease consultation during the afternoon. He reviewed Louise’s medical history and exposure history, and they went over the onset and progression of her diarrhea illness. Dr. Gugliotta stated an awareness of a recent outbreak of “Escherichia coliShiga-toxin-positive disease associated with eating at Panera,” and Louise acknowledged that she had eaten there right before she got sick. He reviewed her admission labs, as well as her treatment to date that included antibiotic therapy. Dr. Gugliotta observed:

Since admission, several things have happened. The patient has developed increasing abdominal girth and ultrasound and other modalities show some ascites. She underwent magnetic resonance imaging (MRI) of the abdomen with and without contrast. This showed a cystic lesion in the body of the pancreas, ascites and findings consistent with enterocolitis. Stool was negative for Salmonella, Aeromonas and Plesiomonas. Stool negative for Clostridium difficiletoxin. Stool showed rare white cells. Stool was negative for Shiga toxin 1, positive for Shiga toxin 2. Campylobacterantigen negative. Ascitic fluid was tapped and is culture negative to date, was performed on March 30, 2018. The patient received ceftriaxone on March 30, 2018, and March 31, 2018. Cell count of the paracentesis: White cells 695 with 53 polys, 3 lymphocytes, 42 macrophages, red cells 6042. Ultrasound of the legs was negative today for deep venous thrombosis (DVT).

Dr. Gugliotta reviewed the most recent lab results that showed Louise had significant anemia and low platelets. He agreed that her progressive thrombocytopenia and anemia, with evidence of hemolysis, were most consistent with a diagnosis of hemolytic uremic syndrome. While Louise’s serum creatinine was not highly elevated, he commented: “The renal function, it should be noted, is off by 50%, noting that she had a nadir level of 0.46 and now it is 0.98.” Dr. Gugliotta requested a renal consultation. Meanwhile, he discontinued Louise’s antibiotics and recommended supportive care only.

Louise was frightened when she learned she needed blood:

… my hemoglobin dropped below 8 requiring me to have 1 pint of blood transfused. A day later it dropped to 6.6 and I was given 2 more pints of blood. Needless to say that made quite an impact on my energy level. The day before I went to the ER I walked 5.75 miles at 13:48/mile. I generally walked 5-6 miles per day or ran 3 miles. Upon return home I was only able to walk about a 1/4 mile and that took me 20 minutes! It was quite frustrating to feel so weak.

Hospital Day 7-8 – nephrology consultation

On April 2, 2018, Bevon Miele, MD came in for nephrology at the request of Dr. Gugliotta. Louise’s labs that morning included a white count of 13,600, hemoglobin 6.6, hematocrit 18.7, platelets 18,000, BUN 23, creatinine 1.09, AST 64, ALT 23, total bilirubin 1.2, low haptoglobin (< 10), lactate dehydrogenase 1462 (up from 1262 on the 1^st).^[5]Her urinalysis, which had been unremarkable on admit, now showed 4+ protein, 3+ blood, and muddy urine sediment with multiple casts, “consistent with acute tubular necrosis.”

At the time of Dr. Miele’s consultation, Louise was in the middle of receiving of blood transfusion of a unit of packed red blood cells (pRBCs). She stated she was still having multiple episodes of diarrhea. Dr. Miele discussed the entities of hemolytic uremic syndrome (HUS) as well as thrombotic thrombocytopenic purpura (TTP), including the role of plasmapheresis, “… should she have thrombotic thrombocytopenic purpura.” Dr. Miele assigned Louise the diagnosis of “acute renal failure due to acute tubular necrosis on the basis of intravascular volume depletion and decreased renal perfusion.” He stated he saw no evidence of glomerulonephritis on direct microscopic evaluation of her urine sediment. Dr. Miele also diagnosed Louise with “hemolytic uremic syndrome secondary to Shiga toxin 2,” adding the comorbidities of hypoalbuminemia, hyperbilirubinemia, elevated liver function tests to the list. He observed that the marked elevation of her lactate dehydrogenase was consistent with HUS vs. TTP.^[6]He requested additional lab tests to include a creatinine clearance and total protein, and he wanted her intake and output closely monitored with direct measurements as well as daily weights. He agreed with the transfusion of pRBCs to increase her intravascular volume and was interested in the results of the ADAMTS13 test already ordered, to rule out TTP, with a plan to repeat blood transfusions based on serial measurements of Louise’s hemoglobin and platelet counts. Louise required another transfusion of pRBCs on April 4^th.

Hospital Day 9-12

On Thursday, April 5, 2018, Louise continued to be plagued with diarrhea, but it was no longer bloody, if still watery, and her abdominal pain was decreasing. She had a headache going on two days that was making her miserable. Her platelets began rebounding and her hemoglobin and hematocrit stabilized.

Louise recalls the worry of finding out something else might be wrong:

During most of my stay in the hospital I was connected to an IV making trips to the bathroom quite a chore particularly early on when the diarrhea was so frequent and urgent. Once the e-coli was discovered, doctors told me they were testing for HUS and something else that I don’t remember but could be fatal. While I am not a worrier, that definitely put a scare in me. The diagnosis of HUS was bad, but a relief at that point. I knew there was still the chance of kidney failure but trusted my doctors to do their best to prevent that. My greatest fear during my stay was kidney failure and needing dialysis. Thankfully, that was never needed.

Over the weekend, Louise continued to feel improvement and did not require another blood transfusion. Her main complaint was boating and gas, and her doctors were concerned about her ascites and likely fluid overload. She was put on Lasix to see if that might help that, with a plan to send her home on an oral form of the medication if it was effective.

 

Louise recovering in hospital

Louise recalls how fluid overloaded she was:

Throughout my hospital stay my body was retaining fluids causing me to be very bloated. I had gained about 20+ pounds of fluid! While I needed to get out of bed and walk, it was very difficult. In fact, I generally had to support my bloated belly with my hands to be able to walk. 10 minutes was about all I could do before needing to lay down. Showering was also a difficult experience. With all that fluid/bloating I was unable to reach my feet and often had to hold on to a railing for balance in the shower. Showering felt so good but was also quite exhausting. I was given intravenous diuretics for 3 days and then 3 days of pills after returning home. After all the fluid was gone I had actually lost about 8 pounds from not having eaten much for the first 8-10 days.

Hospital Day 13 – going home

On Monday, April 9, 2018, hospitalist Nuha Adburahman, DO evaluated Louise for discharge home. She reviewed her lab test results, noting that she had required three units of packed red blood cells during her admission for hemolytic and acute blood loss anemia. Her blood count and platelets were stable, and she no longer exhibited thrombocytopenia. She had continued to produce urine during her admission. Dr. Adburahman believed that the IV fluids and blood transfusions were the cause for Louise’s fluid overload, and the moderate ascites was from low blood albumin. She wanted Louise to continue taking Lasix for three days at home to continue to treat her fluid overload. Louise was currently tolerating a soft diet and was feeling less bloated.

Dr. Adburahman discharged Louise home that afternoon with a prescription for oral Lasix and vitamin and iron supplements. Louise’s discharge diagnoses included “Shiga toxin 2 producing Escherichia coliinfection,” “hemolytic uremic syndrome,” “acute anemia,” “ascites,” “thrombocytopenia,” and associated comorbidities of hypoalbuminemia, hyponatremia, osteoporosis, pancreatic cyst, hepatic cyst, chronic constipation, fatty liver, headaches, acute fluid overload, and hypokalemia.

Pleasant Run Family Physicians

On April 10, 2018, a nurse from Pleasant Run Family Physicians telephoned Louise to see how she was doing, and she reported that she was feeling better. She stated she was planning to get blood work done at their office in a few days, and had appointments lined up with gastroenterology. On the 13^th, Louise’s labs revealed a white count 6.4, hemoglobin 9.9, hematocrit 31.7, platelets 450, BUN 10, creatinine 0l76, AST 17, ALT 18. These tests were repeated on the 20^thand showed improvement in her anemia (Hgb 11.4, Hct 35.2, platelets 359) and stable liver and kidney function.

On May 22, 2018, Louise presented for a visit with Kimberly Martino, PA-C, who deemed her fully recovered from “HUS due to E. coli.” She was not having any diarrhea and she was urinating well without any problems. PA Martino recommended a probiotic to help replete her gut bacteria after having severe infectious diarrhea.

Home, getting better

Louise reflects on her hospitalization and its impact on her life:

After 2 nights of diarrhea, when it turned to bloody diarrhea on 3/25/18, I went to the ER, beginning my 15-day (3/25/18 – 4/9/18) stay in the hospital.

During most of my stay in the hospital, I was in isolation, requiring all staff and visitors to wear gloves and gowns. While this was merely an annoyance to my husband, because it was due to the risk to others as well as me, it meant my daughter was unable to visit as she was pregnant and we did not want to risk anything happening to her. Additionally, once I was diagnosed with HUS, family members were very worried about the risk of kidney failure for me. My illness was particularly worrisome for my mother who is 94. She had also been diagnosed with C. diff so even after I was feeling better, my doctor recommended that I not visit her for quite some time as there was still concern that I would be at risk as my organs were still compromised after what I had been through and my still needed more time to heal completely.

While not directly related to my illness, one of the hardest things I had to deal with during my time in the hospital was the loss of my dog. He was nearly 15 and we loved him so much. My husband was so upset that in spite of being in the hospital, I had to make the arrangements to have our dog euthanized. I was very upset and still regret that I could not be there with him during the procedure. It was difficult retuning home and not seeing him.

Thankfully, throughout this ordeal, I was not at risk of losing my job and did not suffer any wage loss. I was paid during the time I was in the hospital and after being released I was able to work from home for 2 weeks and then 3 hours a day in the office for the following two weeks. I was not able to physically be in the office due to the need to keep legs elevated and frequent rest periods, not to mention eating small meals about every two hours. Working from home provided a distraction from the physical discomfort.

I am uncertain as to whether there are any long-term effects from HUS but will be discussing that with my gastroenterologist. Additionally, there is always a chance of problems from having transfusions. I routinely donate blood every two months and have been told that I cannot donate blood for a year to be sure there are no negative effects from those transfusions.

This was by far the worst experience of my life. The pain and diarrhea were very difficult to endure. And two weeks in a hospital bed is the worst! I am a very active person and it took weeks to regain my strength and stamina. What was particularly bothersome is the fact that 5 people died and that could have been me!

Now that it seems they have determined where this e-coli epidemic originated, I certainly hope they will take steps to prevent future occurrences so no one else has to endure this horrific ordeal.

The causal link between Louise Fraser’s confirmed E. coliO157 infection and romaine lettuce purchased at Panera Bread is clear. On March 20, 2018 Louise purchased and consumed a Fuji Apple Chicken Salad from Panera Bread located in Raritan, New Jersey.

Louise began to experience symptoms consistent with E. coli infection on March 23, 2018. An exposure on March 20 is consistent with an incubation period that averages 3 to 4 days for Shiga toxin-producing E. coli (STEC). A stool specimen collected on March 26, 2018 tested positive for STEC O157:H7, negative for Stx1, and positive for Stx2 at Hunterdon Medical Center. This finding was confirmed at the New Jersey Division of Public Health and Environmental Laboratories. Further genetic testing determined that Louise’s STEC infection was a genetic match to an outbreak “of STEC O157:H7 associated with romaine lettuce/leafy green exposure.” This is most likely about the Yuma, Arizona romaine E. colioutbreak strain (PFGE pattern EXHX01.0047/ EXHA26.0626).

Given Louise’s confirmed infection with STEC O157,her exposure to romaine lettuce within the average STEC incubation period, and confirmation that Louise was related to a multi-state outbreak associated with romaine lettuce during the time of the Yuma, Arizona romaine E. colioutbreak (Outbreak ID: 1804MLEXH-1), Louise was implicated as a case in the outbreak by the New Jersey Division of Public Health and Environment and the Centers for Disease Control and Prevention (ID: NJ___180435).

________________________________________

[1]          Leukocytes are not normally seen in stools in the absence of infection or other inflammatory processes. Fecal leukocytosis is a response to infection with microorganisms that invade tissue or produce toxins, which causes tissue damage. “Test ID: LEU Fecal Leukocytes.” LEU – Clinical: Fecal Leukocytes. Mayo Clinic, n.d. Web. 26 Dec. 2016.

[2]          Ascitesrefers to edema marked by excess serous fluid in the peritoneal cavity. Venes, Donald. Taber’s Cyclopedic Medical Dictionary (Taber’s Cyclopedic Medical Dictionary (Thumb Index Version)) (Page 210). F.A. Davis Company. Kindle Edition.

[3]           Ileusrefers to the loss of bowel motility, occasionally resulting in intestinal obstruction. It is characterized by loss of the forward flow of intestinal contents, often accompanied by cramps in the abdomen, increasing abdominal distention, obstipation or constipation, vomiting, electrolyte disturbances, and dehydration. Ibidat 1196.

[4]          A left shiftis a phrase used to note that there are a high number of young, immature white blood cells (also called “bands” or “stabs”) present. Most commonly, this means that there is an infection or inflammation present and the bone marrow is producing more WBCs and releasing them into the blood before they are fully mature. “Left shift” is a term leftover from when older, standard lab reports displayed the immature cells on the left side of the page. Blumenreich, Martin S. “The White Blood Cell and Differential Count.” Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition., U.S. National Library of Medicine, Jan. 1990, www.ncbi.nlm.nih.gov/books/NBK261/.

[5]          The hemolytic-uremic syndrome (HUS) is defined by the association of hemolytic anemia (low haptoglobin levels, high lactate dehydrogenase levels, and schistocytes), thrombocytopenia, and acute renal failure. Olivia Boyer and Patrick Niaudet, “Hemolytic Uremic Syndrome: New Developments in Pathogenesis and Treatment,” International Journal of Nephrology, vol. 2011, Article ID 908407, 10 pages, 2011. doi:10.4061/2011/908407

[6]          Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) share the morphologic lesion of thrombotic microangiopathy (TMA), characterized by thrombi occluding the microvasculature. The HUS and TTP syndromes overlap clinically; however, certain features have been relied on to distinguish most cases labeled HUS, which is predominantly a disease of children younger than 5 years, from most cases labeled TTP, which is predominantly a disease of adults. Renal manifestations are more prominent than neurologic ones in HUS, whereas neurologic findings are more prominent than renal findings in TTP. Fogo, Agnes B., et al. “Thrombotic microangiopathies.” Fundamentals of Renal Pathology. Springer Berlin Heidelberg, 2014. 135-142.

I was reading on Food Safety News, “Yuma romaine growers hopeful harvest will end without E. coli issues” https://www.foodsafetynews.com/2019/03/yuma-romaine-growers-hopeful-harvest-will-end-without-e-coli-issues/ and could not help but think that what was missing was a story of a customer.  Here one is:

Jordan Anglen is a 24-year-old young man residing in Meridian, Idaho with his girlfriend Josie. Jordan was among those who became severely ill after consuming E. colicontaminated romaine lettuce. On March 25, 2018, Jordan purchased and ate a Chicken Caesar Salad containing E. coli-contaminated romaine lettuce at the Costco Food Court at 2051 S. Cole Rd., Boise, Idaho.

Primary Health Medical Group

On March 29, 2018, Jordan presented to Primary Health Medical Group, where Shannon Bordes, FNP evaluated him for a chief complaint of “diarrhea, back pain, body achy,” which he stated had begun the night before. Jordan described a two-day history of symptoms, which had also included joint pain, lightheadedness, lack of appetite, lower back pain, fever, and chills. He stated he had taken ibuprofen the previous afternoon at 5:30 PM for his symptoms. He was currently tolerating oral fluids and had been able to eat a small amount of food that morning. He had not been vomiting but was intermittently nauseated. On exam, NP Bordes found Jordan afebrile with a mostly unremarkable exam, which was significant mainly for a rapid heartbeat of 100 and a marginally elevated blood pressure of 137/81. He was mildly febrile with a temperature of 99.3ºF.[1]

NP Bordes thought Jordan’s clinical presentation was most consistent with viral gastroenteritis, which seemed to be already improving. She approved the use of Imodium to slow down his diarrhea, advising him to follow a clear liquid diet, and increase his intake slowly with electrolyte-containing fluids. Once his diarrhea was resolved, she told him he could advance his diet to more solid foods. If he had worsening symptoms, such as increasing fevers or abdominal pain, or bloody or dark stools, she advised him to return immediately or go to the ER. Jordan went home and tried to follow the instructions given him by the nurse practitioner, but he only got worse and worse.

St. Luke’s Meridian Medical Center

On March 30, 2018 at 2:45 AM, Jordan presented to St. Luke’s Meridian Medical Center, where Konrad Kessler, MD evaluated him in the emergency department for his worsening abdominal pain, nausea, vomiting, and diarrhea. After vomiting for hours without any intake, Jordan was now experiencing retching and dry heaves, which felt much worse to him than if he had something to throw up. He told the doctor about the clinic visit where he was diagnosed with a virus, but since then he began experiencing abdominal pain “before, after and during” bowel movements. His stool had also turned bloody for the three hours preceding his coming to the ER. Currently, Jordan rated his pain as 10/10 in severity, with was non-radiating and did not get better or worse with anything he tried. He was still urinating normally, as far as he could tell.

On exam, Dr. Kessler found Jordan dehydrated with tacky mucous membranes, and dry and cracked lips. His vital signs were in normal range, and his lungs were clear. Jordan’s abdomen was diffusely tender to even light palpation, and it was especially severe in his left side with rebound tenderness, and tenderness to percussion. His right abdomen was also tender, but less so.

Among the disorders Dr. Kessler thought might be causing Jordan’s symptoms, he considered toxic megacolon,^[2]colitis, gastroenteritis, bowel obstruction, among others. He planned to obtain diagnostic laboratory studies and imaging while they attempted to treat him symptomatically with pain and nausea medications. He started Jordan on intravenous fluids and sent blood, urine, and stool to the lab for analysis.

The lab soon reported a number of abnormalities, including an elevated white blood cell count of 14.59, which contained a predominance of neutrophils.[3] He also had a slightly elevated hemoglobin of 18.1, reflecting his severe dehydration. His kidney function was currently in normal range, with a BUN and creatinine of 18 and 0.91, and his liver function was similarly normal.[4]His lipase was in normal range. His serum electrolytes were slightly abnormal, with his bicarbonate just out of normal range.

At 3:18 AM, radiologist Brian McMahan, MD performed an IV-contrast-enhanced CT of Jordan’s abdomen and pelvis, during which he found no signs of obstruction. Jordan’s appendix was surgically absent, an expected finding as he had it removed in 2013. Dr. McMahan observed thickening of the descending and transverse colon, “likely due to underdistention.” The ascending colon was also inflamed, and there was a trace of free fluid surrounding it. Dr. McMahan thought Jordan’s CT was consistent with mild colitis, although the changes he saw were largely nonspecific.

Dr. McMahan kept Jordan under observation in the ER for an hour and a half, after which he reported that his symptoms were much improved. He declined any pain or nausea medications, feeling that the reversal of his dehydration with IV fluids was helping him enough. The doctor discussed the diagnostic findings from Jordan’s labs and CT scan with him and his mother, and he reassured them that he appeared to have a gastrointestinal illness that should be self-limited. Dr. McMahan deemed Jordan safe for outpatient management and discharged him home from the ER with a prescription for Zofran in case he needed it. He encouraged him to stay as well hydrated as possible and to return if he noticed any blood in his emesis, or he had persistent vomiting, dehydration, or uncontrolled abdominal pain. Jordan left the ER at around 4:30 AM.

Getting worse at home…

Unfortunately, Jordan went home and grew steadily worse. After his initial improvement with IV hydration in the ER, he was unable to keep up with oral fluids, and his diarrhea increased in frequency. Even worse was the rectal bleeding—Jordan’s bloody diarrhea began to contain less stool and more blood, and by 11 PM on the 30^th, it appeared to be only bright red blood. His lightheadedness returned, and he began feeling very dizzy, which alarmed his family.

St. Luke’s Meridian Medical Center – ER – sent home again

On Saturday, March 31, 2018 at 1:02 AM, Jordan returned to the Meridian ER, where Steven N. Wyman, MD evaluated him and sent repeat blood work to the lab. Jordan’s white blood cell count had increased to 22.76 and his platelets began to fall, now measuring 138K. A stool test for toxigenic C. difficilewas negative. Dr. Wyman restarted Jordan on IV fluids and gave him a dose of IV antibiotics (ciprofloxacin). At 3 AM sent Jordan home with a prescription to take oral ciprofloxacin 500 mg twice daily for a week and to see gastroenterologist Mark Mallory, MD on Monday if his symptoms persisted.

Confirmation of Shiga toxinin stool

At 4 AM, the hospital laboratory reported at critical value to the ER that Jordan’s stool had returned positive results for Shiga toxin. Dr. Wyman called Jordan at home and was told that he was still having bloody diarrhea. “I requested that he return to the Emergency Department for reevaluation.”

Return to Meridian ER diagnosed with STEC infection – antibiotics stopped

Jordan arrived back at the ER at 8 PM on April 1, 2018. Dr. Wyman was on duty when he arrived, and he told the doctor that he continued to have bloody diarrhea every 5-30 minutes. Dr. Wyman ordered intravenous fluids and reassessment of his blood work. The lab soon returned results showing an elevated white count of 28.83, and low platelets of 60K. His BUN and creatinine were 25 and 1.32. Dr. Wyman commented that Jordan had now developed “some minor renal insufficiency with a creatinine of 1.32 and thrombocytopenia with a platelet count of 60,000. Bilirubin is also elevated at 4.4.” His transaminases were in normal range. Dr. Wyman again consulted with gastroenterology and the consensus was to discontinue all antibiotics and admit Jordan for supportive care. Jordan’s diagnoses upon leaving the ER were: “Shiga toxin-producing Escherichia coliinfection” (STEC), “Renal insufficiency,” and “Thrombocytopenia.”

Admission under contact isolation – Meridian Hospital Day 1

On April 1, 2018 at 10:41 PM, hospitalist Mary Ann Huntington, MD formally admitted Jordan to the hospital as an inpatient under contact isolation, diagnosing him with “sepsis,” “STEC,” and “AKI.” Dr. Huntington reviewed Jordan’s history of his present bloody diarrhea, which had now been going on for four days, including his two ER visits and now return to the hospital for admission. He continued to complain of diffuse crampy abdominal pain, some nausea, but no current vomiting. Despite not having eaten for four days, he stated he was not hungry. Dr. Huntington noted that the antibiotics that were started had since been discontinued with this admit, since his stool studies returned positive results for Shiga toxin. She addressed his diagnosis of “sepsis,” commenting that it was related to the Shiga toxin producing E. coli— “Shigella, Salmonella, Campylobacterwere negative. C. difficilewas negative.” Dr. Huntington thought Jordan’s acute kidney injury was likely secondary to volume depletion from recurrent diarrhea; however, she thought it was possible that Jordan was developing hemolytic uremic syndrome.

Meridian Hospital Day 2-3 – evolving HUS, oliguria

Hospitalist Meaghen Friel, MD came in to see Jordan during morning rounds on April 2, 2018. He continued to have bloody diarrhea, and his exam was significant for “profound rebound pain.” She checked his morning labs, which showed an improved WBC of 23.57, but a worsening of his acute kidney injury (BUN 32, creatinine 1.42). She noted that he had not had any urinary output in the prior 24 hours. His platelets had dropped to 26K, which increased her concern for HUS, so she ordered an LDH and haptoglobin.[5]

On April 3, 2018, at 1:43 PM, Aaron A. Fearday, MD came in for a nephrology consultation to evaluate Jordan’s acute kidney injury, reviewing his worsening renal function labs. Jordan reported that he was in his usual state of good health until 6 days before, at which time he developed abdominal pain and diarrhea so severe, it caused him to seek care twice in the ER. Jordan stated that he was initially taking Imodium for the diarrhea. Dr. Fearday noted that Jordan’s father was concerned about his son’s nutrition, but Jordan had declined a feeding tube. Dr. Fearday discussed with Jordan and his dad in detail that parenteral nutrition was not a good idea at that time. He agreed with Jordan’s other providers that he had HUS. Dr. Fearday commented in his chart note:

The patient’s labs are all consistent [with] thrombotic microangiopathy given his hemolysis, thrombocytopenia, and acute kidney injury. In the setting of diffused diarrhea and stool culture, Williams will also be seeing the patient later today. His father was concerned that we were ‘not doing anything.’ I explained that we are giving him fluids and we are also closely watching his clinical status. I reiterated that antibiotics and anti-motility agents can often prolong the infection and the symptoms and are not recommended at this time.

Dr. Fearday also discussed with Jordan and his dad that it was going to “… take time for his body to fight this infection. I explained that if the kidney function worsens, we could do dialysis, but I don’t think that there is an indication at this time.” His father wanted to know if they could do dialysis to “ease the burden on the kidney,” and Dr. Fearday explained that dialysis would not achieve that goal: “I explained that dialysis cleans the blood when the kidneys are not working. His mother and father are very anxious about the illness of Jordan. I explained that we are watching his clinical course closely.”

Hematology consultation – platelet transfusion

Travis Williams DO came in for a hematology consultation when it became clear that Jordan was developing hemolytic uremic syndrome. His BUN and creatinine were now 57 and 3.22, and his platelets dropped further to just 13K. His LDH was elevated at 2705. He noted that Jordan was given IV ciprofloxacin in the ER and since taken two days of the oral medication before it was stopped at the beginning of this admit. Jordan stated that he was actually feeling better, although he was having difficulty urinating.

Dr. Williams concurred with Jordan’s diagnoses of  “Shiga Toxin E. coliwith HUS (STEC-HUS) with progressive thrombocytopenia, renal failure, hyperbilirubinemia, elevated LDH.” He noted that Jordan was still having bloody stools, but no fevers, altered mental status or confusion. He saw no current indication for total plasma exchange (TPE) or fresh frozen plasma (FFP) infusions; however, since Jordan was significantly thrombocytopenic, he recommended a platelet transfusion to keep his counts above 20K while currently bleeding.

Jordan received a platelet transfusion that afternoon. Dr. Williams ordered a transfusion of packed red blood cells (pRBCs) if Jordan’s hemoglobin fell below 8 g/dL, and he wanted some other labs checked, commenting: “To be complete I would ensure coags, fibrinogen, and ADAMTS13^[6]have been checked. Typically, HUS is more platelet consumptive as opposed to coagulation factors consumption.” Meanwhile, he advised supportive measures with intravenous hydration and continued renal support by nephrology.

Meridian Hospital Day 4 – continued oliguria

On April 4, 2018, hospitalist Shanna Case, MD evaluated Jordan during morning rounds. He complained of continued incessant bloody diarrhea, describing some 30 episodes during the prior 24 hours, which actually represented a decrease in number. His pain was under control, but he required frequent dosing of narcotic pain medications (Dilaudid). He was unable to tolerate anything orally except for a small amount of water. Jordan was barely producing any urine and was effectively anuric. His mental status appeared intact and he denied confusion, about which his mother agreed.

Jordan was visited by hematology and nephrology. Jordan reported frequent bowel movements that still contained some blood. Dr. Fearday noted that his renal function had worsened overnight (BUN 79, creatinine 4.79). Jordan thought he was producing some urine, but the doctor observed that it was actually very little. He explained that they would assess him daily for the need for dialysis. “There is a chance he may benefit from dialysis in the next day or two if there is no clinical improvement.” Jordan was becoming volume overloaded, and he was hyponatremic as well as oliguric. Dr. Fearday recommended they stop his IV fluids the next day if that did not change. Jordan’s mother was present at his bedside discussed the care plan.

Meridian Hospital Day 5 – marginal urine increase

On April 5, 2018, Dr. Case reviewed Jordan’s morning labs, which continued to reflect sepsis, hemolytic anemia, thrombocytopenia, and worsening renal function, as well as marginal liver dysfunction (WBC 39.94, hemoglobin 9.2, hematocrit 26.1, platelets 21K, BUN 94, creatinine 5.42, AST 61). While his leukocytosis was worse, his tachycardia had improved, and his serum lactate normalized. His diarrhea was also improving, although still frequent, and his stools less bloody. Dr. Case commented that Jordan’s HUS was reported to the Department of Health on the 5^thby nephrology. She noted his platelets were stable overnight, and his hemoglobin was just high enough to avoid a blood transfusion. She commented that nephrology was following his renal function, which continued to worsen secondary to the toxic effect of Shiga toxin Escherichia coli. Improving urine output. Jordan’s urinary output increased somewhat, and she saw no current indication for hemodialysis at that time. He was still hyponatremic and hypervolemic and remained on reduced fluids per nephrology recommendations to address those things.

At 10 PM, Sandra Van Hooser, RN summoned the hospitalist when Jordan began complaining of crushing chest pain to the left side of his chest. The pain did not radiate or get worse with deep inspirations and Jordan did not require supplemental oxygen. He continued to make frequent trips to the bathroom for diarrhea. He had not been measuring his urine output, stating it was too difficult with the diarrhea. Jordan had been suffering with hiccups all day, which was thought to have something to do with the chest pain episode, and the physician did not think he needed to be placed on cardiac monitoring with an EKG.

Meridian Hospital Day 6-7 – blood transfusion pRBCs – improving urinary output

On April 6, 2018, Robert Davidson, MD came in for nephrology, finding Jordan much the same as the day before, including the unrelenting hiccups. He made no changes to his diagnoses or care plan.

Dr. Case came in a little later and evaluated Jordan, who told her that his diarrhea had become bloody again overnight and his abdominal pain was not well controlled, even on the narcotics being given “as needed.” He was feeling very fatigued and lightheaded that day with ambulation. His morning labs showed a WBC 41.57, hemoglobin 7.4, hematocrit 21.1, platelets 24K, BUN 93, creatinine 4.44, and LDH 2776. Dr. Case ordered a blood transfusion of two units pRBC’s (packed red blood cells). She made some adjustments to Jordan’s narcotic pain medication orders, hoping to get his pain under better control. Jordan’s urine output was improving slightly that day.

At 5:47 PM, Dr. Williams came in for hematology/oncology and went over Jordan’s lab results. His mother was at the bedside, and the doctor explained that his extremely elevated white blood cell count was reflective of ongoing bone marrow issues related to hemolytic uremic syndrome, with its associated hemolytic anemic and thrombocytopenia. He observed that Jordan’s elevated LDH and serum ferritin were consistent with hemolysis from Shiga toxin. If Jordan developed fevers, then he would be more concerned and would order blood cultures to rule out a systemic infection. He explained that antibiotics were contraindicated with HUS because they could actually make his condition worse.

Dr. Case came in to see Jordan on April 7, 2018, observing that his urinary output was improving daily. His diarrhea was no longer bloody, and the frequency was down to hourly. He was able to tolerate small amounts of fruit and juice. He stated his pain was better controlled. His lab improved that morning since yesterday’s blood transfusion (WBC 37.07, hemoglobin 8.1, hematocrit 23.0, platelets 28K, BUN 83, creatinine 3.46, AST 215, ALT 56, total bili 3.1, LDH 3168).

Dr. Davidson came in for nephrology, and Jordan expressed a desire to go home. He stated his diarrhea had improved and he was urinating more, hoping that would convince the doctor. Dr. Davidson did not think Jordan’s HUS was getting worse at this point, but his LDH was still very high and probably reflected ongoing hemolysis. He explained to Jordan and his mom that he was too ill to be discharged any time soon.

Meridian Hospital Day 8 – development of neurologic symptoms (myoclonus)

When Dr. Case evaluated Jordan around 8 AM on April 8, 2018, she was happy to see that he was having even less frequent diarrhea (every 2 hours) that continued to be nonbloody, but he still had a very poor appetite and was taking in only a little fruit and juice. He appeared exhausted, and he stated he was not sleeping much. His labs were still markedly abnormal, albeit improving (WBC 31.00, hemoglobin 7.3, hematocrit 21.6, platelets 41K, BUN 69, creatinine 2.65, LDH 2556).

Of greater concern was that Jordan had developed a new neurologic symptom, exhibiting episodes of jerking when he drifted off to sleep. In addition, he had two episodes of nosebleeds overnight; however, his coagulation panel was reassuring. He was still afebrile and denied any confusion or other mental status changes. Dr. Case conferred with neurology, who thought the jerking episodes were probably myoclonus from uremia, although Jordan’s BUN was gradually improving.

Neurology Consultation

At 1:12 PM, neurologist Daniel Abenroth, MD came in to evaluate Jordan. Upon reviewing the history of his symptoms and talking to Jordan and his mom, he learned that he had been having the jerking movements for 2-3 days. Dr. Abenroth did a neuro assessment commented in his chart note:

23-year male who has developed acute myoclonus in the setting of hemolytic uremic syndrome. Uremia itself is a known cause of myoclonus. Though he is producing urine, he’s been clearly dealing with acute kidney injury and HUS, which has also resulted in a number of metabolic abnormalities. His acute myoclonus is likely the result of his HUS, AKI, and metabolic disturbances. My concern for underlying seizures or other causes of myoclonus is low at this time. This myoclonus is typically a self-limited phenomenon that improves as the renal and metabolic disturbances improve. This is unlikely to represent the onset of new chronic condition. Typical symptomatic treatment modalities include Keppra[7]and [benzodiazepines]. Treatment for the myoclonus in his case is not essential (his myoclonus is relatively rare during the day; 3-4 reported episodes today), though treatment could provide symptomatic relief. This was explained to the patient. At this time, he prefers to defer more meds unless his condition fails to improve or worsens.

Seizures – Rapid Response Team (RRT) response

The St. Luke’s Internal Medicine (SLIM) service paged Dr. Abenroth around 8:45 PM in the evening on April 8, 2018, after Jordan had an episode of reported arm twitching while on the toilet. The staff found Jordan on the bathroom floor with twitching arms and legs. Afterward, he appeared to be agitated. The nursing staff and family felt this episode was different and looked more like a seizure instead of myoclonus.

The Rapid Response Team documented Jordan’s seizure episode:

STAFF NURSE FOR UNIT.

Ryan Fox, RN 8:05 PM. I heard a call for “help” from the pt’s room. I was preparing to gown-up where I observed the pt seated on the toilet with his legs extended and leaning his torso and head back while his shoulders and head were being supported by his significant other. The pt appeared to be seizing at that time. I immediately entered the room and took over for the pt’s [significant other] in protecting his head. The pt was having what appeared to be a tonic clonic seizure; his legs and arms were fully extended and the pt was convulsing. The pt had bloody frothy saliva coming from his mouth. Kelly Wolfe, RN, entered the room and I requested that she call a rapid response and get staff assistance.

The seizure lasted approximately 28 seconds from the time I entered the room. I instructed the family to lay down some blankets and a pillow on the ground next to the toilet and the pt was transferred from the toilet to the ground. The pt appeared to be in a post-ictal state after being positioned on the ground; the pt was non-verbal, inactive, and had a distant gaze in his eyes with nystagmus that would not focus on me. Vital signs were obtained and were found to be stable.

CRISIS RN – RAPID RESPONSE TEAM

Lisa Stimpson, RN 8:30 PM. Rapid response called for this patient who had seizure-like activity while on the toilet. Event witnessed by staff and family. Arrived to find patient awake and lying on bathroom floor. Pt had been placed on oxygen and carefully assisted to floor for safety w/o fall or injury except for small bite to lower lip with scant bleeding. Pt appears to be postictal. Not able to maintain eye contact or follow commands, incomprehensible speech, moving all extremities spontaneously. GCS 11. PERRL. Placed green sheet under pt and used lift to return to bed. Seizure pads placed on bed. Family at bedside, however pt remains altered, agitated and tachycardic. Hospitalist came promptly to bedside to assess. Orders for Keppra and brain MRI scheduled for morning. BG 167. Pt now calm. Still not speaking to family but maintaining eye contact. HR trending down to baseline. Keppra infusing.

SLIM EVENT NOTE 8:33 PM

Daniel Orchard, MD. My colleague Sam Gallo PA was paged that the patient may have had a seizure. In brief Jordan Anglen is a 23 yo man here with E. Coli causing HUS, AKI, thrombocytopenia and anemia. He developed myoclonic jerks as a result of the uremia and was evaluated by neurologist. Dr. Abenroth earlier today. The patient chose to defer meds at that time. A full workup for seizure including MRI/EEG was not recommended given the natural course of myoclonic jerks and the likelihood of seizure was low.

When I arrive at the room, the patient’s girlfriend, mother, and father are gowning up to go in and tell me that I’m needed right away because he is having a seizure. The girlfriend tells me he was on the toilet when he started to have jerking movements like earlier today, he also reached out suddenly with both arms grabbing the toilet. There was no head trauma, but he was not responding to questions. On exam, his eyes are not dilated, he is moving all extremities spontaneously, he is purposefully moving his hands in front of his face and seems to be looking at them, he sometimes groans/moans. He had no evidence of head trauma. He doesn’t seem sluggish as is typically found during a post-ictal state. He is tachycardic.

Dr. Abenroth diagnosed Jordan with “probable acute seizure” and started him on Keppra 500 mg twice daily (renal dosing for seizure) and ordered an MRI for the following day. He deferred an EEG for now, commenting, “Whether myoclonus or seizures, we will treat with Keppra. Furthermore, whether myoclonus or seizure, either is likely due to his HUS and several metabolic disturbances. This is unlikely to represent the new onset of a chronic seizure disorder.” If needed for breakthrough seizures, Dr. Abenroth ordered Ativan 1-2 mg intravenously. He planned to see Jordan for a reassessment in the morning.

Jordan not improving after seizure – incontinent of bowel and bladder

After Jordan’s seizure, his family was understandably extremely upset and worried about their son. They soon summoned the nursing staff that Jordan seemed to be getting much worse. At 10:30 PM, Lisa Stimpson, RN called the SLIM service to communicate her concern that, 2.5 hours after the seizure, Jordan remained non-communicative and unable to maintain eye contact or follow commands, and he was now incontinent of bowel and bladder. He would moan rather than speak his answers.

The nurse spoke with both Sam Gallo, PA and Daniel Orchard, MD. The family requested that an MRI be done immediately and not wait for morning. She conveyed a message to the doctors: “Family is very concerned and dissatisfied.” Despite the family’s request, the doctors were not convinced of the need to return to the unit—both felt it appropriate to continue with observation and proceeding with the MRI in the morning as ordered.

Meridian Hospital Day 9 – more seizure activity, incontinence

Shortly after midnight on April 9, 2018, the nursing staff urgently paged hospitalist Mousumi Nandy, MD for another “event” that was still ongoing. Jordan’s mental status appeared to be worsening, with three additional episodes of incontinence of bowel and bladder. His parents were at the bedside and extremely anxious and upset and demanded that Jordan to be seen by a doctor.

Dr. Nandy soon arrived on the unit and spoke with Jordan’s nurse and his family, who told him that Jordan had an observed 28-seconds-long generalized tonic-clonic seizure, in the presence of nursing staff, and following that he was not following any commands, which was a definite change from the time of his first seizure. Prior to the seizure, “… patient was alert awake doing fine.” “Family both parents are very concerned. Mom is wanting to get something done now to find answers regarding his changes.”

Dr. Nandy observed that Jordan was awake but not responding to any verbal or tactile commands. His pupils were reactive and equal. He was unable to cooperate for a neurological exam; however, he moved all four extremities on his own. During Dr. Nandy’s first examination, he observed some “posturing” with Jordan’s right elbow flexed and his hand curled inside, as well as the left hand straight but fist curled inside towards the body. He continued to moan intermittently. During Dr. Nandy’s second examination, Jordan did not exhibit posturing but “… was flinging his hands in the air and then held it over his forehead, resting to move.”

Moved to ICU for seizure watch

Dr. Nandy ordered Jordan moved to the ICU to for seizure monitoring, and he wanted a stat CT of his head to rule out a bleed. He ordered stat labs to include a complete blood count, metabolic panel, and LDH. At 2:32 AM, radiologist John Waltz, MD performed an unenhanced CT of Jordan’s head, which he read as normal.

Dr. Nandy paged neurologist Dr. Abenroth to inform him that he had moved Jordan to the ICU. He explained that Jordan had been persistently encephalopathic since the seizure at 8 PM a few hours earlier, with reported episodes of flexion of his arms (predominantly one arm). He stated that Jordan had remained non-communicative and was receiving renal dosing of Keppra through his IV. “This remains as a significant neurologic change as compared to when I last saw him [yesterday] afternoon, when he was neurologically normal.”

TTP versus HUS – recommendation for plasmapheresis[8]

Dr. Nandy remained concerned for the possibility of TTP^[9]as the cause of Jordan’s neurologic change. Dr. Abenroth addressed this possibility but deferred to hematology and the SLIM team:

TTP can certainly cause a variety of neurologic symptoms, including seizure, encephalopathy, or stroke. Similar changes can also be found in HUS, though significant acute neurologic change remains one of the hallmarks of TTP. The diagnosis of TIP, especially as it relates to the subtle differences between TTP and HUS is beyond the expertise of neurology. As such, I defer ultimate diagnosis of TTP vs. HUS to experts of that disease. However, Neurology recognizes the importance of prompt treatment for TTP with plasmapheresis in cases of suspected disease. As such, if the SLIM and Hematology services have a significantly high suspicion of TTP, then Neurology recommends treatment with plasmapheresis. Plasmapheresis has also been used in cases of atypical HUS. If the SLIM and hematology services feel that patient has atypical HUS, plasmapheresis is also a consideration. Ultimately, the diagnosis of TTP (and whether plasmapheresis is ultimately used) will be deferred to the experts of that condition (hematology and SLIM).

Dr. Abenroth pointed out that a stat head CT was read as normal. He thought it unlikely that Jordan was suffering a stroke, commenting: “In the chance it is stroke, no typical acute stroke treatment is recommended (tPA and aspirin are contraindicated on account of thrombocytopenia) …” In the setting of Jordan’s recent seizure, Dr. Abenroth thought his current condition might simply be post-ictal, but an ongoing seizure was also possible. He recommended that SLIM give Jordan another 2 mg of Ativan now to assess for neurologic change. If he continued to have persistent neurologic symptoms despite the dosing of benzodiazepines, along with additional time to recover from a possible post-ictal state, then Dr. Abenroth recommended that Jordan be transferred to Boise early in the morning (about 8 AM) so that continuous EEG monitoring could be initiated immediately.

After speaking with Dr. Abenroth, Dr. Nandy discussed Jordan’s clinical presentation with the hematologist on call, Dr. Alluri. He expressed his concerns about Jordan’s sudden change of mental status in a patient with HUS and whether he needed to be started on plasmapheresis. “At this point her recommendation was to continue to watch him, since his labs are improving, she will talk to Dr. Williams from hematology who had seen the patient earlier to follow up and decide whether patient would benefit from plasmapheresis or watchful waiting.”

Jordan’s parents were present for the consultations, and Dr. Nandy talked with them at length about their son’s care plan. He ordered the placement of a Foley catheter at 4:39 AM to deal with Jordan’s continued incontinence.

In ICU and not improving – tachycardic and febrile to 101.7ºF

At 8 AM on April 9, 2018, Shanna Case, MD and nephrologist Robert Davidson, MD came in to evaluate Jordan in the ICU, noting that he had been transferred there during the night because of seizure activity. The nursing staff indicated that he had been febrile that morning. His morning labs were in and continued to reflect sepsis, renal dysfunction associated with HUS, and some degree of liver dysfunction (WBC 30.55, hemoglobin 8.8, hematocrit 25.1, platelets 62, BUN 62, creatinine 2.26, AST 132, ALT 79, LDH 2405). Jordan was tachycardic with heart rates ranging from 117-128, with at least one oxygen desaturation down to 88%. The doctors reassessed Jordan’s differential diagnoses, which now included “HUS-TTP versus status epilepticus[10]versus less likely stroke.” They continued his seizure treatment with Keppra, adding Vimpat[11]pending implementation of continuous EEG monitoring.

Neurology consulting recommended a trial of plasmapheresis “… due to clinical decline per discussions with hematology, nephrology.” Upon review of Jordan’s labs, the doctors noted that that his ADAMST13 had come back normal and his complement levels were low, making atypical HUS unlikely. His renal function, while still significantly impaired, was improving steadily and he continued to produce greater amounts of urine. He was currently running a fever of 101.7ºF, but the doctors continued to avoid giving him any antibiotics. They continued his narcotic pain medications and anti-emetics.

Transfer to St. Luke’s Boise for cEEG and plasmapheresis

Travis Williams, DO came in for hematology at 8:14 AM, noting Jordan’s seizure activity, high fevers, and confusion. Given Jordan’s increasingly critical status and move to the ICU, his care team was of the consensus that he should be transferred to Boise for a higher level of care, where he could receive continuous EEG monitoring and be started on plasmapheresis, although Jordan was considered to have typical D+HUS and not atypical HUS.^[12]Rather, Dr. Williams’ recommendation to start plasmapheresis was based on Jordan’s change in mental status, which he felt was directly related to Shiga toxins. “Schistocytes seen on peripheral smear. Elevated LDH and a ferritin consistent with hemolysis from Shiga toxin.” He discussed this with nephrologist Dr. Davidson, who concurred, and they contacted the critical care team in Boise with a plan to begin plasmapheresis as soon as he got there.

St. Luke’s Boise Medical Center – Hospital Day 9 – ICU Day 1 – TPE 1

On April 9, 2018, Jordan was transferred to St. Luke’s Boise Medical Center some 10 miles away by ambulance. The interfacility transport was initiated at 8:57 AM and the ambulance crew arrived at his bedside shortly thereafter. Just prior to moving Jordan, he became extremely agitated and began pulling at his IV lines and Foley catheter, requiring him to be sedated for the ride with Dilaudid. His care was turned over to the ICU team in Boise at 10:25 AM.

Dr. Abenroth met Jordan in the Boise ICU after he was transferred, along with nephrologist Tyler Harris, MD. He was still poorly responsive; his eyes were open, but he was unable to follow any commands or speak. His admission diagnoses included “acute myoclonus, secondary to HUS,” “possible seizures, secondary to HUS,” “hemolytic uremic syndrome,” “encephalopathy, septic-metabolic,” and “possible non-convulsive status epilepticus.” The ICU team conferred over the question as to whether Jordan had TTP:

The SLIM and hematology services maintain that this is most consistent with HUS. Patient will still undergo [therapeutic plasma exchange] in the small chance this is TTP.[Regarding] his encephalopathy, my highest suspicion is that he either has a severe septic metabolic encephalopathy or having seizures. If in fact he has TTP, stroke is a possibility. However, with his thrombocytopenia, neither aspirin or TPA is appropriate. Thus, MRI brain is not essential at this time. I have a low suspicion of CNS infection at this time. He already has a known reason for a fever, and his WBC count continues to improve daily without antibiotics.

Dr. Abenroth continued Jordan on Keppra 500 mg IV every 12 hours, Vimpat 200 mg IV every 12 hours, and deferred a brain MRI for the time being. They also deferred a lumbar puncture at that time. Of note, Jordan’s blood cultures obtained at Meridian were negative for growth of any bacteria.

Insertion of dialysis catheter in preparation for TPE

Later that afternoon, Dr. Harris performed the insertion of a temporary hemodialysis (“trialysis”) catheter under sedation by interventional radiology, in order to accommodate therapeutic plasmapheresis. The catheter was placed into Jordan’s right internal jugular vein, with the tip terminating in the inferior vena cava.

Jordan underwent his first plasmapheresis later that day.

Hospital Day 10 – Boise ICU Day 2 – TPE 2 – another blood transfusion

On April 10, 2018, Robert Davidson, MD came in for nephrology at 8:06 AM, noting that Jordan had undergone a therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) the day before. He was still running a fever of 101.5ºF that morning, but his labs were improving, including his leukocytosis and renal function, but he continued to exhibit severe hemolytic anemia (WBC 18.43, hgb 6.9, hematocrit 20.9, platelets 99K, BUN 48, creatinine 1.78.). Dr. Davidson planned daily [TPE] for at least five days. He commented that “the literature suggests use of eculizumab[13]in this setting,” indicating that he had spoken with hematologist Dan Zuckerman, MD about that and would revisit the issue at some point.

Critical care intensivist Scott Link, MD came in at 8:46 AM, observing that Jordan’s mental status was unchanged overnight. He was hoping to see some improvement after the first plasma exchange. Dr. Link reviewed Jordan’s labs and commented that most values were improving, with the exception of continued severe anemia, for which he was to receive a blood transfusion of pRBCs that day. A continuous EEG was in process and they were awaiting an assessment of that by neurology. Meanwhile, Jordan continued to receive regular doses of Keppra and Vimpat as ordered.

Improvement in mental status

Dr. Zuckerman visited Jordan for hematology just before noon, finding him awake and making purposeful movements, including tracking with his eyes intermittently. He and Dr. Link had just made the decision to proceed with eculizumab but, given Jordan’s slight signs of neurologic improvement, his mother wanted to hold off on the drug for another 24 hours. Meanwhile, the doctors confirmed Jordan’s immunization status since eculizumab would increase his risk of acquiring an infection. If Jordan showed no further neurologic improvement or worsened by the next morning, they planned to initiate the infusion.

Dr. Abenroth came in to see Jordan at 12:22 PM and reviewed the continuous video EEG started the day before. He was happy to see the improvement in his mental status, which included the ability to follow simple commands that morning. He was also less agitated. Dr. Abenroth discussed the EEG with the epileptologist, who identified no seizures, “only encephalopathic pattern.” Jordan’s encephalopathy also looked somewhat improved on the tracing, and so Dr. Abenroth decreased his seizure medications that day (Vimpat to 100 mg twice daily, Keppra unchanged at 400 mg twice daily) and monitor him for seizure activity. Pharmacy notified the doctors that Jordan’s eculizumab was ordered and was expected to arrive in the next 24-48 hours; however, Jordan never required the administration of the medication.

Hospital Day 11 – Boise ICU Day 3 – TPE 3 – more seizure activity

On April 11, 2018 at 2 AM, the nursing staff paged the critical care to Jordan’s bedside when his mother noticed him with increased twitching and feared he was about to have another seizure. However, his neurologic exam was stable with no new changes other than the twitching. Unfortunately, by 4 AM, Jordan was clearly exhibiting seizure activity, with an observed episode of stiffening of his extremities and unresponsiveness to stimuli. The nurse administered IV Ativan as ordered prior to contacting the ICU attending.

Sogol Nowbar, MD responded to the page and observed the video recording of Jordan, confirming the nurse’s observations at 4:08 AM. Jordan was currently “somnolent and “likely post-ictal.” There were no obvious EEG changes, however, and there had been no respiratory compromise. Dr. Nowbar asked the nurse to update neurologist Dr. Kashirny in order to determine whether any additional anti-seizure therapy was needed or repeat imaging advised. She did so, and received no new orders.

Another seizure

At 3:51 AM, when the nursing staff entered Jordan’s room to draw his morning labs, they approached his bedside and attempted to orient him to time and place. She asked Jordan if he was in pain, to which he nodded “no,” but while she was checking his urinary output, Jordan quickly moved his left arm above his head and started grunting. The nurse described that Jordan’s jaw became rigid and blood tinged sputum started coming from his mouth. She rapidly summoned the Rapid Response Team.

Multiple personnel soon arrived in Jordan’s room, who observed him with mild body rigidity. He then became unresponsive and began high pitched grunting. His heart rate increased to the 140’s, but his blood pressure remained in normal range, as did his oxygen saturations, throughout the episode. Jordan was administered additional IV Ativan during the episode. Within 30 minutes of the seizure, Jordan opened his eyes in response to his name, but his affect was flat. He was moving all extremities voluntarily.

Dr. Davidson came in for nephrology at 7:31 AM and learned of Jordan’s apparent seizure a few hours earlier. He thought Jordan’s mental status was improving, despite the seizure. Hospitalist Michael D. Madison, DO arrived shortly thereafter and determined that the red frothy sputum observed by the nurse was caused by Jordan’s biting down on his lip during the seizure.

Improving mental status

Dr. Zuckerman came in for hematology/oncology at 10 AM and also observed that Jordan appeared to be doing better, “… although had another seizure.” He wondered about “primary epilepsy.” At 1:55 PM, Dr Abenroth arrived to see Jordan for neurology and reviewed the details of his morning seizure activity and, upon looking at the cEEG tracing, confirmed that Jordan had indeed suffered an actual seizure. He, too, wondered whether Jordan had an underlying seizure disorder, “probable epilepsy,” besides the encephalopathy related to his HUS. He thought Jordan’s encephalopathy was “septic-metabolic” and improving. He commented in his chart note:

He has been severely encephalopathic; differential diagnosis includes septic-metabolic encephalopathy vs seizures. Less likely consideration stroke. In discussion with the epileptologist about the EEG pattern, there is legitimate concern that patient actually has an underlying seizure disorder beyond acute symptomatic seizures from his condition. Though his HUS can certainly be a precipitant (and likely is for patient) of acute seizures and still likely is for Jordan, his EEG has features concerning for concomitant epilepsy.

Though the emergence of his seizures only at the time of his critical medical condition (with no prior medical history of seizures) raises the question of whether this truly represents epilepsy, the EEG was concerning enough where it is most prudent to treat for now as though this is a primary generalized epilepsy. In the future, long-term outpatient evaluation will be necessary to further clarify this diagnosis and treatment. This was explained in detail to the patient and family.

Dr. Abenroth increased Jordan’s anti-seizure medications to Keppra 1000 mg every 12 hours and ordered a brain MRI after the current EEG was complete. He continued his Vimpat 100 mg twice daily.

Later in the afternoon, Jordan failed a swallow test when speech/language therapist Jennifer Wood, SLP came in to evaluate him. The ICU team felt Jordan needed to be started on total parental nutrition (TPN[14]); however, his family objected and refused the initiation of TPN that night. They expressed a concern about his infectious and volume overload risks and felt their son was improving and hoped he would pass the swallow test the next day. The nurse conveyed the family’s concerns to the ICU staff and held Jordan’s TPN until they could meet with the family. Jordan continued with daily therapeutic plasma exchanges without difficulty.

Hospital Day 12 – Boise ICU Day 4 – TPE 4

On April 12, 2018, Dr. Davidson came in for nephrology in the morning, finding Jordan alert and vocalizing his responses to questions. He was no longer having loose stools. His morning labs reflected improvement (WBC 16.72, hemoglobin 7.8, hematocrit 23.2, BUN 35, creatinine 2.17). Dr. Davidson continued Jordan’s orders for TPE that day and the next with fresh frozen plasma, then he wanted to discontinue the treatments. Jordan’s mom noticed some twitching during the night, which were relieved with Ativan. She indicated that he had been talking and was more interactive since the night before, and he was asking for something to eat and drink. Unfortunately, when Dr. Madison came in for the hospitalist service, he observed that Jordan was unable to pass a swallow evaluation with SLP the day before. Pending today’s evaluation, he approved Jordan to advance his diet to oral fluids and soft solids. If neurology were to discontinue his cEEG, Dr. Madison thought Jordan could be transferred out of the ICU.

Mari Beth Stein, NP came in for oncology/hematology at 9 AM and reviewed Jordan’s labs, noting that his platelet count was now in normal range and his creatinine was almost back to normal. Jordan’s dad asked her about shortening the plasmapheresis, but she told him she was committed to the five days as laid out by nephrology. She did state that Jordan was not going to need the eculizumab.

At 9:38 AM, Jordan passed a swallow evaluation and was approved for full liquids and thin solids, as long as aspiration precautions were followed (“sit upright, 1:1 assist, single sips”) and they were attempted slowly.

Dr. Abenroth came in for neurology during the afternoon and reviewed Jordan’s seizure activity from the day before with Dr. Kashirny. “It was a clear seizure. There were also interictal features in a pattern that is classic for generalized epilepsy disorders. He has continued to have epileptiform activity intermittently that is responsive to benzodiazepines.”

Dr. Abenroth continued to opine that Jordan’s acute myoclonus was secondary to HUS, but he probably had an underlying seizure disorder. Because he continued to have intermittent myoclonic activity with associated EEG abnormalities on the cEEG tracing, and because he was responsive to benzodiazepines, Dr. Abenroth ordered regular dosing with clonazepam; 1 mg that afternoon and 1 mg at bedtime. He wanted to continue with the EEG tracing, and his Keppra and Vimpat as ordered. He continued to order Ativan for breakthrough myoclonic or seizure activity, and his Vimpat could be increased to 200 mg twice daily if that occurred. He continued Jordan’s orders for daily plasmapheresis for at least that day and one more.

Hospital Day 13 – Boise ICU Day 5 – TPE 5

On April 13, 2018, Christopher Keller, MD came in for nephrology at 8:32 AM and observed that today would be Jordan’s fifth day of five days of therapeutic plasma exchange therapy. He was happy with Jordan’s morning labs, which showed significant improvement in his Shiga toxin HUS, with a lower LDH, improved kidney function, and normal platelet count. He did not cancel today’s TPE but thought it should be the last one needed. Hematology/oncology signed off the case that morning.

No more cEEG monitoring – moved out of the ICU

Dr. Abenroth came in for neurology and reviewed Jordan’s cEEG tracings for all five days he had been in the ICU. By day 5, he observed that Jordan’s EEG continued to show improvement over 24-48 hours and was dramatically improved by the end of Day 4. On Day 5, he identified an “essentially unremarkable background presented as posterior alpha activity with a large amount of normal sleep background.” There was no epileptiform activity noted on the last day of the EEG. Dr. Abenroth was satisfied that this improvement was a pattern and that the continuous monitoring could be discontinued. He cautioned Jordan and his parents that, as he was clinically sick in the ICU with what was potentially juvenile myoclonic epilepsy, this abnormality needed to be re-evaluated when Jordan had completely recovered from his acute illness in order to make a final diagnosis of potential epilepsy.

At 11:22 AM, Jordan was moved out of the ICU after his EEG was disconnected and moved to a regular medicine bed.

At 5 PM, Jordan underwent an MRI of his brain, both IV contrast enhanced and unenhanced, during which radiologist Steven Marx, MD identified a normal appearing brain and dura, with no hemorrhage, edema, or mass effect, and normal vascularity.

Boise Hospital Day 14 – removal of dialysis catheter

On April 14, 2018, Sergei Kashirny, MD came in for neurology, finding Jordan awake and alert. He was observed to be following commands reliably and was fully conversant and speaking coherently. Jordan had experienced no seizure activity in the prior 24 hours, and Dr. Kashirny decreased his Vimpat to 50 mg twice daily for two days, with orders to discontinue the medication at that time. He continued Jordan’s Keppra 1000 mg twice daily, as well as his Ativan to be used as needed, and clonazepam at bedtime.

Dr. Keller came in for nephrology and ordered the discontinuation of Jordan’s temporary dialysis catheter, as he would no longer be needing therapeutic plasma exchange therapy. He reviewed his lab work and observed that his renal function panel was all in normal range and he was urinating well. Dr. Keller signed off Jordan’s case for nephrology.

PT, OT, ambulating the halls…

Michael Madison, DO came in for the hospitalist service during the afternoon, and Jordan told him he was feeling “really good” that day. He was awake and alert and very talkative, and asking if he could go home. He was eating and wanted to walk, although he admitted to feeling unsteady on his feet. Jordan was having some headaches that were thought to be medication overuse vs. withdrawal headaches. Neurology was working on weaning him off the benzodiazepines, and also moving away from narcotic medications for pain relief. He was advised to use acetaminophen IV if he needed something for his headaches. Although Jordan’s renal function had rebounded, he was still severely anemic and required another transfusion of pRBCs that day for a hemoglobin of 7.2. His electrolytes were in balance.

Physical and occupational therapy visited Jordan that evening and recommended that he be discharged to inpatient rehabilitation when medically appropriate to leave standard hospital care. He demonstrated decreased upper extremity strength and activity tolerance and was working with both PT and OT to address those deficits. PT noted that he was overall slow-moving and easily distracted, requiring cues to stay on topic and task. “Initially with walking he was scissoring and stumbling. With a walker he was the same but not understanding why he was having a hard time walking a straight line. With cues, he still struggled and, if he was distracted, he could not get right back on task.”

Boise Hospital Day 15-19 – preparing for discharge to rehab

On Sunday, April 15, 2018, Dr. Madison came in for the hospitalist service and continued transitioning Jordan to oral medications, which included Keppra and Vimpat, the latter of which was about to be discontinued in two days. He was advanced to a regular diet. Natasha Pappas came in for case management to discuss with Jordan and his mom his discharge to rehab, which could occur as soon as the next day. They discussed preferred rehab facilities, settling on St. Luke’s Rehab as their first choice. If Jordan had his way, he would just head home in his seriously deconditioned state, but his mom and the therapists convinced him of the utility of building his strength and stamina before doing that. His mom wanted to make sure that, wherever Jordan went, they could monitor his blood in case he needed more transfusions.

Dr. Madison resumed discharge discussions with Jordan and his parents the next day, and his dad was concerned about how somnolent the anti-seizure medications made him. However, he understood the important of seizure prevention at least for the time being. Jordan still exhibited generalized weakness, but he was ambulating the halls and working hard at PT and OT.

On April 17, 2018, Dr. Madison observed that Jordan was very drowsy, which he attributed to a recent Keppra dose. He continued to be weak and unsteady on his feet, but he was not having any seizures. His labs continued to exhibit improvement (WBC 8.08, hemoglobin 8.2, hematocrit 25.0, platelets 238K, BUN 28, creatinine 0.98) and his blood cultures had not grown any bacteria. He was eating and drinking without difficulty, and he was having normal urinary output and bowel movements.

Jordan was growing very bored and wanted to get out of the hospital. He worked daily with PT, OT, and SLP, the latter of which was focusing on memory strategies, attention tasks, and safety awareness, among other cognitive issues that had suffered from his long critical illness. By the 19^th, Jordan was progressing towards his self-care goals, although he was still limited by decreased insight and occasional safety awareness. He exhibited occasional impulsiveness but was able to self-correct without cues (“this may be pt’s baseline due to being young and active”). He was able to perform grooming at the sink with close supervision. His swallow function was near baseline, and SLP was able to discontinue therapy at that time. PT worked with him on higher balance exercises and cognition for safe transition to home.

Boise Hospital Day 20 – getting ready to leave for rehab

On April 20, 2018, hospitalist Allyson Komori, DO evaluated Jordan for discharge from the hospital to sub-acute inpatient rehabilitation. She thought he was ready for transfer to St. Luke’s Rehabilitation Hospital, where they would continue working with him on ongoing strengthening and improvement in his stamina for a safe transition to home. Dr. Komori discharged Jordan from the hospital with the following diagnoses:

Principle Final Discharge Diagnosis:

1. STEC (Shiga toxin-producing Escherichia coli) infection

Secondary Discharge Diagnoses:

1. Hemolytic uremic syndrome
2. Seizure disorder with myoclonus
3. Acute renal injury
4. Metabolic encephalopathy
5. Dysphagia
6. Protein calorie malnutrition
7. Hemolytic anemia
8. Thrombocytopenia
9. Hypokalemia
10. Hypernatremia
11. Generalized weakness

Transferred to St. Luke’s Rehabilitation Hospital

Clifford L. Tenley, MD received Jordan into inpatient rehabilitation on April 20, 2018 at 1:07 PM, for “ongoing restorative care,” after his recent diagnosis of Shiga toxin producing Escherichia coli(STEC) infection.Jordan and his family were by now well aware and shared with Dr. Tenley that his STEC HUS illness began with the consumption of contaminated romaine lettuce. Dr. Tenley thoroughly reviewed the onset and progression of Jordan’s illness and hospital course before he was discharged. Jordan was currently taking Keppra 1000 mg three times daily, as well as clonazepam 1 mg at bedtime for seizure prophylaxis.

St. Luke’s Rehab Day 2-3

On April 21, 2018, Jordan started physical therapy, and he was alert and oriented and independent of transfers in his room. He had a “ground pass,” but his family had to be with him to use it. Jordan was ambulatory throughout the unit without the use of an assistive device, with his nurse as standby assist only. The nurse noted that Jordan had a steady, balanced gait.

Dr. Tenley came in to see Jordan on April 22, 2018 and was happy to see him doing extremely well. He had no nausea, vomiting, diarrhea, or constipation. He was eating lunch and consuming his entire tray. He was able to take a shower on his own that morning, but he commented that his left leg felt “drunk.” He told the doctor he was hoping to be discharged the next day. Dr. Tenley observed “marked improvement overall in the patient’s condition and status at this time. He likely could be discharged in the very near future if not tomorrow.” Jordan was still anemic on the 20^thwith a hemoglobin of 8.7 and hematocrit of 26%. Dr. Tenley wanted to make sure that he would not be returning to work for at least another week once he was discharged home.

St. Luke’s Rehab Day 4 – going home

On April 23, 2018, case manager Amy Alderman was notified by Dr. Tenley that Jordan was ready for discharge from rehab. She talked with Jordan and learned that he lived in a duplex with his girlfriend and two roommates. Although both she and the roommates would be able to assist him, Jordan was planning to go to his parent’s home when no one was available to be with him the first few days. He stated that he worked at Costco and they were going to put him on light duty until he was ready to get back to his normal, heavier work.

Shannon C. Boyer, NP came in to discharge Jordan from the rehab unit at 3:08 PM. She went over his discharge medications with him and instructions for outpatient follow-up with his physicians, starting with hematologist Dr. Williams on May 1. Jordan’s vital signs were normal and stable, and he was exhibiting no severe symptoms from his ongoing anemia. He was discharged that afternoon.

St. Luke’s Hematology Outpatient Clinic

On May 1, 2018, Jordan presented for an outpatient visit with Travis Williams, DO.  Dr. Williams wanted to see him in follow-up of his thrombocytopenia. Jordan had blood work done that day, which showed a WBC 5.26, hemoglobin 10.0, hematocrit 30.0, and platelet count 182K. Jordan’s main complaint was the side effects of his anti-seizure medications, especially the clonazepam at night, which made him feel very sedated and “quasi out of body experience.” Otherwise, he felt he was regaining his strength after his acute illness. Dr. Williams was happy with Jordan’s hematologic recovery and did not think he needed any other follow-up than a recheck of his CBC in a month.

St. Luke’s Family Health Clinic – Meridian – establishing PCP care

Jordan established care with PCP Rebecca Locke, DO on May 10, 2018. Jordan was interested in getting back to normal, and he explained that he could not drive or drink because of the medication he was on. He hoped to get off the medication.

Dr. Locke reviewed Jordan’s records and observed that he had been placed on Keppra and clonazepam following seizures while hospitalized with E. coli. She went over his hospital course with him, discussing everything that had happened to him. He told her that he had a neurology appointment scheduled for the 23^rd. Dr. Locke documented all of Jordan’s hospital diagnoses and his current state of recovery from each. She wanted to make sure he knew he needed another CBC in about a month, as recommended by the hematologist.

Dr. Locke discussed seizure follow-up recommendations with Jordan and that he needed to follow state laws about a return to driving, which set guidelines for how long he had to wait after a seizure. She was not sure about Idaho’s law, so she advised Jordan to avoid driving until his neurologist gave him the okay. She also deferred to neurology about continuing his anti-seizure medications until they advised it was okay to discontinue them. Meanwhile, she discussed the importance of yearly physicals and to do the follow-up with specialists as recommended when he was discharged from the hospital.

St. Luke’s Neurology – sobering precautions

On May 23, 2018, Jordan went to see Sergei Kashirny, MD for his first neurology follow-up since discharge. Jordan was still on clonazepam at night, and Keppra twice daily. Dr. Kashirny wanted Jordan to continue on his current doses of those medications. If he remained seizure-free for the next 2-3 months, then the doctor was willing to discontinue the clonazepam and continue Jordan on Keppra only. At that point, he planned to repeat an EEG in about 3-6 months to evaluate for any signs of primary generalized epilepsy. Jordan’s mother was with him at this visit, and Dr. Kashirny spent time with both of them to answer their questions and talk about seizure precautions. He did not want Jordan to drive for three months after his last seizure, and he advised him against working on heights/ladders, swimming unsupervised, taking baths (take showers instead)—i.e., to avoid any situation where, should he lose consciousness, either he or someone else could be injured. Dr. Kashirny reviewed “SUDEP” (sudden unexplained death in epilepsy) and emphasized the importance of staying compliant with his anti-epileptic medications. He advised Jordan that, if he had a seizure lasting 5 minutes or more, had back-to-back seizures, or seizures without a prompt return to baseline level of consciousness, 911 should be summoned to take him to the nearest emergency room.

Jordan returned to see Dr. Kashirny on August 2, 2018 for a follow-up visit. He denied any seizure activity or myoclonic jerks. He stated he was currently taking Keppra twice daily (1000 mg each time) and clonazepam 0.5 mg at night. He admitted to some chronic anxiety. Dr. Kirshirny continued with the same plan as delineated at Jordan’s May visit, planning to repeat an EEG to make sure no further seizure activity was present. He advised him to continue taking the Keppra at the current dose but to stop the clonazepam. If he noted any myoclonic activity, he wanted to restart it at the same once daily dose as before. Jordan had his “adult awake/drowsy/sleep” testing done on August 28, 2018 at the EEG laboratory, which Dr. Kashirny interpreted as a normal exam by Dr. Kashirny. His report read: “There are no focal lateralizing or epileptiform features.” In a final comment, he cautioned: “Normal EEG does not exclude a diagnosis of epilepsy. Please correlate clinically with EEG findings.” Dr. Kashirny wanted to see Jordan again in six months.

2019 Neurology Outpatient Visit

On January 22, 2019, Dr. Kashirny saw Jordan in his office for a follow-up visit. Jordan reported no seizure activity or myoclonic jerks, currently on a dose of Keppra short acting 1000 mg twice daily. Jordan was diligent about taking his medication but reported an occasional lapse in dosage. Dr. Kashirny recommended that he continue on the Keppra for at least the next 12-18 months. If he stayed seizure-free during that time, he wanted to repeat an EEG and then slowly discontinue the medication if the test picked up no epileptiform activity. At this point, Dr. Kashirny could not clearly rule out a seizure disorder, potentially “juvenile myoclonic epilepsy.” Dr. Kashirny started him on a slightly increased dose of Keppra, utilizing the extended release form (Keppra XR) of 750 mg to take three times daily (2,250 mg total) instead of the short acting 1 gm tablets twice daily (2,000 mg total). He offered Jordan the option of a one-time nightly dose to improve compliance.

Aftermath

Jordan’s girlfriend Josie reflects on his E. coliO157:H7 HUS illness:

I feel like more than anyone I’ve had to see how much this has affected Jordan, how many aspects of his life have changed, or been lost. Anyone who knows Jordan knows he’s an overthinker, doesn’t just jump into a situation but analyzes every aspect of what could go wrong. He’s good at making sure a situation doesn’t turn bad, if he has a say in it.

Ever since he got sick, he’s had no control in his life. From his job, to coming home, to even mentally and physically, I can see how much this is draining from him. The one place he has the most control is work, but how in control and productive can you be when you’re working around possible epilepsy. His own work duties are handed off to someone else until he’s cleared to perform them. So he’s stuck having to deal and rely on others and put the control in their hands.

He comes home from work exhausted cause his body isn’t used to 40-hour work weeks after lying in a hospital bed for a month without food.

And when he does come home to rest, it’s not home because we’re living in the middle of construction. We didn’t have the time to see all our options, to make sure we were getting into a good living situation. We were trying to avoid being homeless.

I could go on and on. He lost 20 pounds coming out of the hospital but hasn’t had a kitchen to be able to eat a good home cooked meal since he got out. He had to get a new car battery because he wasn’t able to drive his car, so the battery died. He hasn’t been able to drink beer because of the seizure meds he has to take.

Because of those seizures, I’ve watched my boyfriend forget Christmas, I’ve watched him forget time with his family, I’ve watched this man I love forget our anniversary. Because of those seizures, I’ve watched [him] forget his proposal to me twice.And have had to watched how devasted and scared he was that he couldn’t remember. Losing your memory isn’t something small. You’re losing a part of you every time you try to remember. And he has no control in getting those parts of him back.For someone who tries so hard to make sure things go right, to do the right thing, his life shouldn’t look so out of his control.

__________________

[1}        Normal vital sign ranges for the average healthy adult while resting are:

• Blood pressure: 90/60 mm Hg to 120/80 mm Hg.
• Breathing: 12 to 18 breaths per minute.
• Pulse: 60 to 100 beats per minute.
• Temperature: 8°Fto 99.1°F (36.5°C to 37.3°C)/average 98.6°F (37°C)

[2]          Toxic megacolonis a marked enlargement of the colon, esp. the transverse colon. Clinically, tachycardia, and leukocytosis occur. There may be abdominal tenderness, a palpable abdominal mass, confusion, cramping, and change in number of bowel movements per day. Venes, Donald. Taber’s Cyclopedic Medical Dictionary (Taber’s Cyclopedic Medical Dictionary (Thumb Index Version)) (Page 1480). F.A. Davis Company. Kindle Edition

[3]          Neutrophiliarefers to an increase in the number of neutrophils in the blood (e.g., as a result of inflammation, infection, corticosteroid drugs, or malignancies). Ibidat 1620.

[4]          Reference ranges for this lab: WBC 3.80-11K, hemoglobin 13.7-17.5 g/dL, hematocrit 39-55%, platelets 150-420K, BUN 9-20 mg/dL, creatinine 0.66-1.25 mg/dL, AST 17-59 U/L, ALT <50 U/L.

[5]          Jordan’s haptoglobin was reported as low at <10 mg/dL and his LDH elevated at 2776 U/L. The hemolytic-uremic syndrome (HUS) is defined by the association of hemolytic anemia (low haptoglobin levels, high lactate dehydrogenase levels, and schistocytes), thrombocytopenia, and acute renal failure. Olivia Boyer and Patrick Niaudet, “Hemolytic Uremic Syndrome: New Developments in Pathogenesis and Treatment,” International Journal of Nephrology, vol. 2011, Article ID 908407, 10 pages, 2011. doi:10.4061/2011/908407

[6]          ADAMTS13 deficiency =<10%. Jordan’s level was 78%. In nearly all patients, aHUS can be distinguished from TTP on the basis of an ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) enzyme activity measurement. It is essential that aHUS and TTP be differentiated quickly, as they require markedly divergent treatments. The standard treatment for TTP is plasma exchange, a therapy that has no role for patients with a diagnosis of aHUS established by ADAMTS13 activity levels. http://www.hematologyandoncology.net/files/2013/02/ho1012_sup171.pdf

[7]          LEV (aka levetiracetam, brand name Keppra) is used in the treatment of seizures; epilepsy; bipolar disorder; neuralgia; new daily persistent headache, and belongs to the drug class pyrrolidine anticonvulsants.”LEV 500 Pill – levetiracetam 500 mg.” LEV 500 Pill – levetiracetam 500 mg. Drugs.com, n.d. Web. 31 Jan. 2017.

[8]          Plasmapheresisis a process that filters the blood and removes harmful antibodies.  It is a procedure done similarly to dialysis; however, it specifically removes antibodies from the plasma portion of the blood.  Antibodies are part of the body’s natural defense system which help destroy things that are not a natural part of our own bodies, like germs or bacteria. In therapeutic plasma exchange, using an automated centrifuge, filtered plasma is discarded and RBCs along with replacement colloid (eg, donor plasma or albumin) are returned to the patient.Kaplan, Bernard S et al. “Current treatment of atypical hemolytic uremic syndrome” Intractable & rare diseases research vol. 3,2 (2014): 34-45

[9]          Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) share the morphologic lesion of thrombotic microangiopathy (TMA), characterized by thrombi occluding the microvasculature. The HUS and TTP syndromes overlap clinically; however, certain features have been relied on to distinguish most cases labeled HUS, which is predominantly a disease of children younger than 5 years, from most cases labeled TTP, which is predominantly a disease of adults. Renal manifestations are more prominent than neurologic ones in HUS, whereas neurologic findings are more prominent than renal findings in TTP. Fogo, Agnes B., et al. “Thrombotic microangiopathies.” Fundamentals of Renal Pathology. Springer Berlin Heidelberg, 2014. 135-142.

[10]        Status epilepticus(SE) is a medical emergency associated with significant morbidity and mortality. SE is defined as a continuous seizure lasting more than 30 min, or two or more seizures without full recovery of consciousness between any of them. Cherian, A., & Thomas, S. V. (2009). Status epilepticus. Annals of Indian Academy of Neurology, 12(3), 140–153.

[11]        Vimpat (Lacosamide) is used either alone or in combination with other medications to prevent partial epileptic seizures. https://www.pdr.net/drug-summary/Vimpat-lacosamide-580

[12]         HUS is classified in 2 subgroups: HUS associated with a foodborne infection with Shiga toxin-producing Escherichia coli(STEC+) and atypical HUS (aHUS), or STEC-HUS. McCoy, Nicole, and Donald J Weaver. “Hemolytic Uremic Syndrome with Simultaneous Shiga Toxin Producing Escherichia Coli and Complement Abnormalities.” BMC Pediatrics 14 (2014): 278. PMC. Web. 31 Jan. 2017.

[13]        Eculizumab (Soliris) is the only agent approved for the treatment of non–Stx-HUS. The FDA approved eculizumab for the treatment of non–Stx-HUS in 2011. Eculizumab is a humanized monoclonal antibody against C5 that inhibits the activation of terminal components of complement.Volokhina, E., et al. “Pharmacokinetics and pharmacodynamics of eculizumab in individualized treatment of atypical HUS.” Pediatric Nephrology. Vol. 31. No. 10. 233. Springer, 2016

[14]        TPN by definition is nutrition given intravenously. It typically consists of dextrose, amino acids, emulsified fats, trace elements, vitamins, and minerals to patients who are unable to assimilate adequate nutrition by mouth.Because TPN solutions are concentrated and can cause thrombosis of peripheral veins, a central venous catheter is usually required. Venes, Donald. Taber’s Cyclopedic Medical Dictionary (Taber’s Cyclopedic Medical Dictionary (Thumb Index Version)) (Page 1650). F.A. Davis Company. Kindle Edition.