Case Study: Complex, and Potentially Deadly
The following case study was used by James P. Keating, MD, MSc, medical director, St. Louis Children’s Hospital Diagnostic Center, and his co-editor, Andrew J. White, MD, division director of pediatric rheumatology/immunology, as part of the “Patient of the Week” (POW) series. Many of the POW case studies cover uncommon illnesses, or common illnesses with unusual symptoms that can be overlooked. If you would like to be added to the POW e-mail distribution list, send an e-mail message to jkeating@wustl.edu or white_a@wustl.edu.
WUSM 4: Chris Markham
PL2: Stephanie Grissom
GI: Robert Rothbaum
PL3: Kyle Schulz
H/O: Gayle Murray/Lisa Madden
A 21-year-old female withileocecal Crohn’s disease (stable for two years) with CC: fever, malaise and anorexia. T intermittently elevated for three weeks.
HPI: With progression of the symptoms in the CC: she had T 104F and was admitted to a county hospital.
Medications: Azathioprine 100 mgm/day.
PE: Jaundice. Liver 4 cm BRCM and spleen at LCM.
Lab: WBC 1.8m, N 76%, Hgb 6.5,Plts 79,000,Bilirubin 6.0, AST 384, ALT 131, alkaline phosphatase 1015 (<125), Alb 1.9, Mono spot positive.
Hospital course: Her azathioprine was discontinued. Her symptoms persisted and the alk ptase steadily increased. She was transfused eight times due to low hemoglobins. TPN was instituted. Endoscopy (X2)showed blood in the lumen of the transverse colon, but no focal bleeding point was found.Needle biopsy of a cervical lymph node was nondiagnostic (reactive hyperplasia or lymphoproliferative process.) EBV PCR was positive. Negative: RPR, Viral hepatitis panel, HIV, CMV, malarial antibody, toxoplasmosis, influenza, and bacterial cultures of throat, blood, feces, urine. At one point, she developed SOB and hypoxemia with small pleural effusions and was placed in the ICU. CT of neck showed multiple nodes, hepatosplenomegaly and pleural effusions compatible with noncardiogeneic pulmonary edema.
Other studies after transfer to SLCH and suspicion that she may have hemophagocytic lymphohistiocytosis (HLH):
Ferritin (10-120)
Day 1 – 1,101 (This initial value was elevated but not in the range usually seen in HLH.)
Day 4 – 1,460
Day 5 – 3,500
Day 6 – 11,300
Immunoglobulins
IgG 2240 mgm/dl (700-1200) [Immunoglobulins are usually in the normal range in HLH; elevations in this range are found in Crohn’s disease.]
Cytokines
IL-2 r was 30,061 (45-1105) [This reflects the marked increase in cytokines characteristic of the pathophysiology of HLH.]
Diagnosis: Hemophagocytic lymphohistiocytosis (HLH).
Plan: Version of HLH 2004 protocol (Survival of >50% has been reported compared to earlier, much-worse outcomes.)
Dexamethasone
Etoposide
Cyclosporine
VP-16
Comment: This is a condition with marked increase in cytokine and histiocyte activity. The specific cause is not clear, but it has been associated with EBV infection and immunosuppression, two factors present in this young woman. It also occurs in a familial form and has been reported in association with Kawasaki S., Hermansky Pudlak S, Chediak-Higashi S. There is a published case report of HLH of a patient with Crohn’s disease and EBV infection.
The hemophagocytic pathology, which can be found in bone marrow, lymph nodes or elsewhere, is often not seen on first sampling of tissue (as in the lymph node biopsy). Now that there is an intervention of value, early diagnosis has become important.
Case Study Comments
From Gregory Storch, MD, SLCH director of infectious diseases:
I would like to make a couple of comments about this case from the ID standpoint .First, the positive mono spot test is provocative. EBV is well known to be associated with HLH. However, the mono spot by itself is not diagnostic of EBV, particularly in light of her immunoglobulin abnormalities. For that reason, this would be a good case to measure the EBV viral load. Usually we do that test on whole blood, in light of the fact that EBV is ordinarily highly cell-associated. However, in this case it would be helpful to measure the EBV load in the plasma as well.The presence of EBV DNA in the plasma is generally taken as evidence of a very actively replicating infection.If she has plasma viremia, it would make sense to treat her with acyclovir.While acyclovir has been shown be clinically ineffective in routine cases of infectious mononcucleosis, it does have activity against EBV and does exert an anti-viral effect, which might be of benefit in a case like this in which active viral replication may be occurring. The second point is that we have seen a number of cases of HLH associated with severe monocytic ehrlichiosis. In fact there can be quite a bit of overlap in the clinical manifestations of ehrlichiosis and those of HLH, but in the cases I am thinking of, we have seen hemophagocytosis in bone marrow aspirates, convincing us that the patient had HLH as a complication of ehrlichiosis.
An interesting paper published in the Journal of Infectious Diseases several years ago showed that in the related disease human anaplasmosis (AKA human granulocytic ehrlichiosis), some degree of “macrophage activation” resulting in elevation of the serum ferritin, was seen in most cases, and the height of the ferritin elevation seemed to be a reflection of the severity of the disease process.Parvovirus B19 is the other infection that we have seen at SLCH associated with HLH.
From Shalini Shenoy, MD, SLCH director, bone marrow transplant program
The HLH protocol is an international protocol developed by the Histiocytosis Society and incorporates agents active against the pathology that is HLH. The backbone of therapy is with steroids, cyclosporine and VP16, and intrathecal therapy if the CNS is affected.
The idea is to put the patient in remission from the inflammatory symptoms of the disease. Allogeneic stem cell transplantation is considered curative for the spectrum of HLH disorders—HLH, Chediak-Higashi, X-linked lymphoproliferative disorder, Griselli syndrome, etc.—and a genetic defect in the perforin and related pathways of NK cell function is detected in approximately 60% of cases.
Acquired hemophagocytic lymphohistiocytosis can manifest after infections that overwhelm the immune system (typically EBV)—even in these situations, depending on the severity of the presentation and the predisposition to recurrence, therapy as above may be indicated (it is generally thought that the infection brings the immune disregulation to light).
