Facilitator Version
# 28 – Approach to the Immunocompromised Patient in the
Inpatient Setting
Created by Dr. Charles Pizanis
Objectives:
1. Be able to identify fevers in a patient with neutropenia and indications for
various antibiotics
2. Develop a differential of and diagnostic approach to diarrhea in an
immunocompromised patient
3. Recognize overwhelming post-splenectomy infection and its common clinical
scenario
References:
1. Freifeld AG, Bow EJ, Sepkowitz KA, et. al. Clinical practice guideline for the
use of antimicrobial agents in neutropenic patients with cancer: 2010 update
by the Infectious Diseases Society of America. Clin Inf Dis 2011;52(4):e56e93.
2. Krones E, Högenauer C. Diarrhea in the immunocompromised patient.
Gastroenterol Clin N Am 2012;41:677-701.
3. Sabatino AD, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic
states. Lancet 2011;378:86-97.
4. General recommendations on immunization: recommendations from the
Advisory Committee on Immunization Practices (ACIP). MMWR
2011;60(RRO2):1-60.
CASE 1
Mr. R is a 62-year-old male with recently diagnosed HIV-negative diffuse large B-cell
lymphoma who recently completed cycle 1 of chemotherapy with R-CHOP seven
days ago. He presents to the Emergency Department with a fever of 102.3 degrees
Fahrenheit at home.
Patient’s presenting vitals are as follows:
Temperature 39.2 degrees Celsius / Heart rate 88 / Blood pressure 122/80 /
Respiratory rate 12 / Oxygen saturation 94% on Room Air
His initial laboratories reveal the following:
CBC: WBC 0.3, hemoglobin 9.8, platelets 128
Differential: absolute neutrophil count 100, absolute lymphocyte count 150,
absolute monocyte count 40, absolute eosinophil count 10
Chemistries: Na 138, K 4.2, Cl 105, HCO3 27, BUN 12, Creatinine 0.9
LFTs: Total protein 5.1, albumin 2.5, AST 42, ALT 54, Alkaline phosphatase 80, total
bilirubin 1.0
The Emergency Department contacts you to admit the patient.
Which clinical syndrome does the patient have and why?
Febrile Neutropenia
What does this syndrome often represent?
This syndrome usually represents that a patient has an infection.
How does one calculate the absolute neutrophil count?
While most laboratories report the absolute neutrophil count (ANC) on a CBC
differential, some do not. It is important for the clinician to know the following
formula:
ANC = WBC x (% polymorphonuclear cell count +%bands)
What ANC constitutes neutropenia?
While there are several definitions for what constitutes neutropenia, the traditional
ANC below which febrile neutropenia is considered is an ANC < 500 cells/mm^3.
What other items on history are important to know?
Does the patient have any localizing symptoms? – These may indicate the location of
the infection.
Does the patient have any existing central lines or ports? - The presence of indwelling
devices such as central lines and ports pose a potential nidus of infection and should
be screened for in all patients in whom infection is considered.
Does the patient complain of any oral symptoms? - The presence of mucositis which is
often a complication of systemic chemotherapies is associated for the development
of bacteremias from coagulase-negative staphylococci and viridans group
streptococci.
Did the patient receive antibiotic prophylaxis? – Antibiotic prophylaxis (often with a
fluoroquinolone) is usually recommended for patients with an ANC less than or
equal to 100 cells/mm^3 expected to last greater than 7 days. If patient had been
receiving such an agent but still developed febrile neutropenia, suspicion for
resistant organism should be raised.
What is the anticipated duration of neutropenia? - Patients with prolonged
anticipated neutropenia (i.e. greater than 7 days) are considered higher risk for
complications related to febrile neutropenia.
Back to the Case:
Patient states that other than the fever which he noticed at home as well as some
mild fatigue and a dry cough over the past several days, he does not have any other
complaints. He denies having any ports or central lines. He states he was given an
antibiotic after his chemotherapy, but he cannot remember its name. A complete
review of systems is negative except for those mentioned above.
On exam, he appears in no acute distress. He is alert and oriented to interview.
Head and neck exam does not demonstrate any oral lesions or lymphadenopathy.
Chest exam reveals a normal sounding heart with lungs that are clear to
auscultation. He does not have any abdominal tenderness or organomegaly. Skin
exam does not demonstrate any ports, central lines, or exanthems.
What are some risk factors which make a patient with fevers and neutropenia
at higher risk for complications?
Several historical and clinical factors increase the risk of complications in
neutropenic patients with fevers. Some examples include profound neutropenia
(ANC less than or equal to 100 cells/mm^3 expected to last more than 7 days); the
presence of comorbid conditions including: hemodynamic instability, oral or
gastrointestinal mucositis, neurologic changes, presence of intravascular catheters,
new chest infiltrate, new hypoxia, and chronic lung disease; hepatic insufficiency;
and renal insufficiency. Individuals at high-risk should be admitted for intravenous
antibiotics. The Multinational Association for Supportive Care in Cancer Risk-Index
Score (MASCC) is one scoring system which attempts to screen for high-risk patients
requiring intravenous instead of oral antibiotics.
Which additional investigations are indicated at this time?
All patients with neutropenic fever should receive at least two sets of blood cultures.
Additional laboratories and investigations should be driven by clinical symptoms
and suspicion for locus of infection. Given his mild cough, chest imaging is indicated.
Which empiric antibiotics should be started at this time?
All high-risk patients with febrile neutropenia should be placed on
antipseuodomonal beta-lactam agent such as cefepime, a carbapenem (meropenem
or imipenem-cilastatin) or piperacillin/tazobactam. The decision for additional
agents is based on clinical suspicion for other infections (see below).
When is vancomycin indicated?
Vancomycin (and other agents directed at aerobic gram positive cocci) are not part
of the standard initial empiric regimen for febrile neutropenia unless certain clinical
situations: evidence of severe sepsis, hemodynamic instability, suspected catheterrelated infection, skin or soft-tissue infection, pneumonia, or severe mucositis if
ceftazadime is used as anti-pseudomonal beta-lactam and fluoroquinolone
prophylaxis has been given. Based on what we know of the patient, vancomycin is
not yet indicated.
When should antifungals be used?
Antifungals should be considered in patients with persistent fever after 4-7 days of
appropriate antibiotics and/or in whom an invasive fungal infection is suspected or
proven.
Back to the case:
Patient is has two sets of blood cultures obtained, is started on cefepime, and
admitted to the hospital. His evaluation including chest x-ray and urinalysis is
negative for source of infection. On hospital day 3, patient defervesces and both sets
of blood cultures return positive and grow a pan-sensitive Eschericia coli. He is
transitioned to oral ciprofloxacin. After one day of monitoring, he is discharged to
home. He is seen at follow up after completion of antibiotics and endorses no
further fevers.
CASE 2
Mr. S is a 48-year-old male with a history of combined kidney-pancreas
transplantation five years prior for end-stage renal disease and diabetes mellitus
type 1 who presents to the Emergency Department with a several week history of
loose stools and abdominal pain. Patient states he had been in his usual state of
health prior to onset of increasingly loose stool. He states he is stooling four to five
times daily (normal for patient is once every other day). He has noticed some
streaky blood in his stools as well. He states his abdominal pain is intermittent,
mostly in the lower aspects of his abdomen and is not made better or worse with
food, defecation or movement.
Vital signs are as follows:
Temperature 37.5 degrees Celsius, heart rate 70 and regular, blood pressures
110/68 sitting and 90/60 standing, respiratory rate 10, oxygen saturation 94 % on
room air.
CBC shows a WBC of 4.5, hemoglobin of 11.0 (baseline 11-12), hematocrit of 33
(baseline 35-38), platelets of 180.
What historical items should be sought in the history regarding the etiology of
diarrhea?
Recent travel history – a history of recent travel may give a clue toward underlying
etiology. With a detailed travel itinerary, the clinician may be able to zero in on
frequently implicated organisms endemic to certain areas.
Sick contacts - a history of contact with individual(s) with similar symptoms may
give a clue about the etiology. Infectious diarrhea, particularly when caused by a
virus, is often transmissible.
Water source – individuals with sources of unpurified water may be more likely to
be infected. Well water as well as stream water is associated with several bacterial
and parasitic agents.
Recent new medications or changes in medications – Many medications are
associated with the development of diarrhea. Of particular note are several
immunosuppressive medications. Mycophenolic acid derivatives (mycophenolate
mofetil – CellCept; and mycophenolic acid – Myfortic) which are often used in
immunosuppression after solid organ transplantation have a known side effect of
diarrhea. Calcineurin inhibitors such as tacrolimus, sirolimus, and cyclosporine are
also associated with the development of diarrhea. Recent antibiotic exposure is
associated with the development of antiobiotic-associated diarrhea as well as
Clostridium difficile infection.
What is the differential of infectious diarrhea in this patient?
The differential of infectious diarrhea in this patient includes those entities seen in
the general population as well as those seen more commonly in immunosuppressed
patients. Common agents seen in the general population include bacterial causes
(Salmonella spp, Shigella spp, Camplyobacter spp, C. difficile, E. coli). Viral causes
included Norovirus, Adenovirus, and Rotavirus. Parasitic agents include Giardia
lamblia, Entamoeba histolytica.
Some additional infectious entities to consider include those seen more commonly
in immunosuppressed individuals. Bacterial causes seen more frequently in
immunosuppressed patients include Mycobacterium avium complex. Parasitic causes
seen mostly in immunocompromised patients include Cryptosporidium spp,
Cytoisospora belli, Cyclospora spp. Fungal causes include microsporidia, Histoplasma
capsulatum, Candida spp. Viruses usually only seen in immunocompromised
patients include Cytomegalovirus (CMV) and Herpes Simplex Virus (HSV).
What is the differential of non-infectious diarrhea in this patient?
The non-infectious differential of diarrhea in an immunocompromised patient is
similar to that of an immunocompetent patient with several important exceptions.
Inflammatory bowel disease, irritable bowel syndrome, malabsorption syndromes
are all common considerations for patients with chronic diarrhea.
One important syndrome seen in patients with a history of solid organ
transplantation is graft-versus-host disease (GVHD). While more common after
autologous hematologic stem cell transplantation, GVHD has been reported in
individuals with a previous solid organ transplant and is associated with a poor
prognosis.
Medications are often implicated in patients on immunosuppression. As mentioned
above, mycophenolic acid derivatives and calcineurin inhibitors can cause diarrhea.
Back to the case:
Patient denies any recent travel, sick contacts, or medication changes including
antibiotics. He states his water source is purified city water.
Because of patient’s immunosuppressed state and need for intravenous fluids, the
patient is admitted to the hospital for further evaluation and treatment of his
diarrhea and dehydration. His Myfortic is held.
What testing is indicated for the evaluation of patient’s diarrhea at this time?
There are several approaches to this patient’s diarrheal evaluation. Because
infectious causes are high on the differential, the patient should have testing
directed at identifying a causative organism. CBC with differential should be
obtained to evaluate for leukocytosis, leukopenia, and any other cell line
disturbances. Blood cultures should be obtained to assess for presence of
bacteremia. Stool studies including stool culture, stool ova and parasite exam, C.
difficile assays, and stool guaiac. Serum CMV PCR should also be obtained. HIV
status should be ascertained. Given patient’s immunosuppression and
symptomatology, abdominal imaging should also be performed.
Back to the case:
A rectal with stool guaiac is performed and is positive for occult blood. CT of the
abdomen and pelvis demonstrates some distal colonic wall thickening without
abscess or free air. He is started of IV antibiotics for presumed infectious colitis.
Blood cultures, stool cultures, stool ova and parasite exam, C. difficile assay, and HIV
1/2 antibodies are all negative, however.
On hospital day 4, patient’s diarrhea continues. Because his preliminary workup for
infectious colitis is negative, Gastroenterology is consulted for endoscopy. The
patient undergoes a colonoscopy. During endoscopic inspection, several ulcerated
lesions with some patchy erythema are noted. Biopsies are taken and return
positive several days later with “owl eye inclusions” on hematoxylin and eosin
(H&E) staining.
What is the significance of the biopsy results?
Owl eye inclusions on H&E staining are highly specific of CMV infection. They
represent intranuclear inclusions and are eosinophilic. Intracytoplasmic inclusions
can also be seen in CMV-infected cells
How does CMV colitis present clinically?
There is a range of presentations of CMV colitis. Patients often present with lowgrade fevers, weight loss, anorexia, abdominal pain, and diarrhea which is often
bloody. Occasionally patients will present with fulminant colitis with surgical
abdomen and circulatory collapse.
Does this represent a primary CMV infection?
The patient’s presentation is suggestive of reactivation of latent CMV infection.
There is a very high seroprevalence of CMV in the general population and most
symptomatic cases of CMV infection represent reactivation of latent infection.
How is CMV colitis treated?
While there are several agents with activity against CMV, ganciclovir is the
treatment of choice for CMV colitis.
What is a major side effect of ganciclovir which requires close laboratory
monitoring?
Ganciclovir is associated with bone marrow suppression in which case foscarnet is
usually a second line agent
Back to the case:
Patient is diagnosed with CMV colitis. He is started on intravenous ganciclovir
5mg/kg IV twice daily for 2 weeks. His diarrhea, abdominal pain and blood in his
stool eventually resolve and he is discharged home.
CASE 3
Ms. L is a 28-year-old female who presents to the Emergency Department with
fevers, headache, and rigors. She states that she had been in her usual state of
health until three days ago when started to notice some body aches. She
subsequently started to feel warm at which time she found her temperature to be
102 degrees Fahrenheit. Her past medical history is significant only for a motor
vehicle accident in her early 20s during which time she sustained some abdominal
trauma and had to have her spleen removed. She otherwise denies any medical
issues. She denies current or previous use of illicit drugs or alcohol and is not
sexually active. She denies being around anyone with similar symptoms.
Vital signs at presentation to the ED are as follows:
Temperature 40.2 degrees Celsius / Heart rate 110 / Blood pressure 70/60 /
Respiratory rate 12 / Oxygen Saturation 94% on 5L nasal cannulus (86% on room
air)
On physical exam, patient appears fatigued. Her head and neck exam does not
reveal any abnormalities. Cardiac exam shows tachycardia but is otherwise normal.
Her lung exam exhibits some crackles in the middle lung fields on the right with
some E-to-A changes. The remainder of the exam is normal.
Blood and sputum cultures are drawn, and the patient is started on intravenous
vancomycin and pipericillin/tazobactam. Despite several intravenous boluses of
normal saline, the patient remains hypotensive and vasopressors are started. The
Emergency Department contacts you to admit the patient to the medical intensive
care unit.
What aspect of her past medical history is concerning in this case and why?
Her history of splenectomy is of concern as it increases her risk for certain
infections.
To which infectious agents is patient susceptible because of her past medical
history?
Patients with a history of splenectomy or functional asplenia are at risk for
infections caused by encapsulated bacteria. The most common encapsulated
bacteria causing human disease include Streptococcus pneumoniae, Neisseria
meningitidis, Hemophilus influenzae, group B Streptococcus spp, Salmonella typhi,
and Klebsiella pneumoniae.
Name some other conditions wherein hyposplenism is observed.
Sickle cell anemia, celiac disease, inflammatory bowel disease, HIV infection, postbone marrow transplantation, alcoholic liver disease. Each of these conditions
effects splenic dysfunction in various different ways.
How does hyposplenism increase one’s risk for infection by the above
organisms?
While the spleen exhibits its immunologic function in several ways, the primary
reason by which encapsulated organisms are initially more virulent in individuals
with hyposplenism is thought to involve an impaired antibody response.
Encapsulated organisms evade host opsonization and resultant phagocytosis, and
the force the host to utilize antibodies, particularly IgM produced by memory Blymphocytes which reside in the spleen, for initial infection response. Individuals
with hyposplenism have a weakened antibody response to such bacterial
inoculation and are thus susceptible to infection.
Which vaccinations should the patient have received after splenectomy and
when are they recommended?
1. Pneumococcal vaccine –2 doses of PPSV separated by 5 years for individuals
aged ≥ 2 years
2. H influenza type B (Hib) conjugate vaccine
3. Meningococcal vaccine- 1 dose of MCV4 (Menactra) for individuals aged 2-55
years OR 1 dose of MCV4 (Menveo) for individuals aged 11-55 years. 1 dose
of MPSV4 for individuals aged ≥ 56 years. Revaccination at a five year
interval is recommended for high risk individuals.
If possible, vaccines should be given at least 14 days before splenectomy. Otherwise,
they are recommended as soon as patient is stable to receive them.
What are some initial investigations which should be performed at this time?
WBC 18,000, Hemoglobin 12, Platelts 350,000, differential PMNs 90%
Chemistries: Na 138, K 4.6, Cl 100, HCO3 11, BUN 42, Creatinine 2.2 (baseline 0.6),
Glucose 180
LFTs: Total protein 7.0, albumin 3.6, AST 55, ALT 60, alkaline phosphatase 90, total
bilirubin 0.8, direct bilirubin 0.3
UA: spec grav 1.02, protein trace, leukocyte esterase positive, nitrites negative, wbc
3, rbc 1, blood none
Lactate: 4.2
Urine beta-HCG: negative
Chest xray shows a right middle lobe infiltrate.
Blood cultures x2 pending
Back to the case:
You admit the patient to the MICU and place a central venous catheter and arterial
line for hemodynamic monitoring. She requires high doses of norepinephrine and is
started on vasopressin as well.
On hospital day 2, patient continues to be hypotensive. She becomes increasingly
tachypneic and acidotic and is intubated for impending respiratory failure. Both
sets of blood cultures that same day return positive for Streptococcus pneumoniae
which is susceptible to ceftriaxone. Vancomycin and pipericillin/tazobactam are
discontinued and patient is placed on ceftriaxone.
What is the name of the condition from which patient is suffering?
Overwhelming post-splenectomy infection (OPSI). This is a dreaded complication of
post-splenectomy states. Mortality rates have been reported as high as 50-75%.
The most common organism identified in OPSI is S. pneumoniae.
Back to the case:
By hospital day 6, patient’s blood pressures and acidosis continue to worsen despite
aggressive efforts by the ICU team. A family meeting is called and patient is
transitioned to comfort care measures. She is taken off of the ventilator and expires
later that evening.
MKSAP 16 Questions:
Hematology Oncology Question 124 – Answer A
Nephrology Question 10 - Answer B
Infectious Disease Question 92 – Answer D
Post Module Evaluation
Please place completed evaluation in an interdepartmental mail envelope and
address to Dr. Wendy Gerstein, Department of Medicine, VAMC (111) or give to Dr.
Patrick Rendon at UNM Hospital.
1) Topic of module:__________________________
2) On a scale of 1-5, how effective was this module for learning this topic? _________
(1= not effective at all, 5 = extremely effective)
3) Were there any obvious errors, confusing data, or omissions? Please list/comment
below:
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
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4) Was the attending involved in the teaching of this module? Yes/no (please circle).
5) Please provide any further comments/feedback about this module, or the inpatient
curriculum in general:
6) Please circle one:
Attending
Resident (R2/R3)
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