Another Consumer with Acute Kidney Failure Linked to Spring 2018 Romaine E. coli Outbreak

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 (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).

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[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.

Republished with permission from Bill Marler and Marler Clark. Copyright (c) Marler Clark LLP, PS. All rights reserved.