Febrile Neutropenia

Quick post today from morning report where discussed a patient with a hematologic malignancy post chemotherapy presenting with fever and an absolute neutrophil count (ANC) of 0.3.

Remember that Febrile Neutropenia is a syndrome, not on its own a diagnosis, and we still need to do our job to find the cause/source.

Definition of Febrile Neutropenia is:
- Fever 38.3 x 1 or > 38 on multiple occasions (ie > 1 hour apart)
- Neutropenia (< 0.5 or < 1.0 with expected nadir less than 0.5)

Degree of neutropenia correlates with likelihood of developing fever, such that an ANC of 0.25-0.5 within approximately 7 days, there is ~30% chance of fever, and if ANC less than 0.25, 
chances can go up to ~90%.

Infection is always the concern, and a source will be found in approximately 30% of cases.

History and Physical (as always) is key! and remembering that these patients have no immune response reminds us that they might not have the ability to mount a dramatic inflammatory picture and so their signs/symptoms might be subtle.

Things to consider specifically:
- mucositis (oral, GI tract)
- dentition
- line: often these patients will have indwelling lines for chemotherapy. 
- abdominal findings
- subtle findings might warrant further investigation with imaging.

Full physical exam....
- inspect lines for: erythema, tenderness, purulent discharge (expressible?), induration, fluctuance
- DRE is contraindicated in patients with febrile neutropenia.

At risk organisms in general
- Gram negatives including Pseudomonas
- Gram positives especially if concerned with line infection
- C. Diffiicile, resistant organisms - depending on case.

Empiric therapy is aimed towards the above, and so often will consist of broad spectrum antibiotics including Pseudomonas coverage. Often times "double coverage" for Pseudomonas will be started, this is more for the concern that one of the agents might have resistance against it, so thus (hopefully) ensuring that one of the agents will work. 

Who gets Vanco? (not absolute, and certainly will vary depending on local micro patterns)
- concern for line infection
- known MRSA positive
- mucositis on prior fluoroquinolone proophylaxis (selects out for Viridans Group Strep with high MIC for penicillin).

When to stop?
- Consider stopping or stepping down once ANC normal, and afebrile x 48 hours
- Treat any identified source as you normally would

What if fever persists?
- if after day 4 fever continues consider antifungal coverage, especially if receiving prophylaxis

A word on typhlitis/neutropenic enterocolitis:

Mucous membrane damage can occur with chemotherapy (some more than others) which can lead to bacterial invasion of GI wall.
Major criteria for NEC would be
- Fever
- ANC < 0.5
- Bowel wall thickening > 4mm

These patients will have abdo pain, cramping, diarrhea.
Important to think about C.Diff in these patients in addition to above, and to get surgery consultation early if warranted. 

Full IDSA guidelines here. Remember that local micro patterns will alter protocols.

Myeloma kidney 

Multiple myeloma is a plasma cell dyscrasia, that will result in the production of pathogenic, abnormal paraprotein. 

Diagnosis is made looking for a paraprotein in the serum via an SPEP +/- IFE, the same can be done in the urine with a UPEP. Also serum free light chains and looking for the presence of Bence Jones protein in the urine is part of the workup. Bence Jones proteins are seen by mixing the urine sample with SSA that causes protein denaturation. This may be caused by the presence of albumin, but if the urine dip is negative for protein (specifically albumin), but mixing with SSA causes precipitation, then the is likely non-albumin protein (ie light chains).

Also remember that in renal failure, the serum free light chains will be elevated, not necessarily diagnostic, but what will be helpful is if the ratio is disproportionate.

There are many causes of renal disease with multiple myeloma. 

There can be 'indirect' harms: 

Hypercalcemia, and volume depletion.

Bisphosphonate therapy and kidney injury.

Possibly from recurrent infections.

Myeloma itself can cause direct damage to the different parts of the kidney: 

Tubulointersititial disease is common such as with myeloma kidney, acquired fanconi, and AIN. Glomerular disease can be seen with Ig deposition disease, AL amyloid, as well as cryo and GN.

Couple words on specific entities: 

“Myeloma kidney”  or cast nephropathy: 

Light chains in tubules. Can cause intrarenal obstruction as it precipitates. Fragmented casts seen on path.

Acquired Fanconi due to PCT dysfunction

Light chain disease causing inability to reabsorb glucose, uric acid, phosphate, bicarb, amino acids

Monoclonal Ig deposition disease: can be heavy or light. Proteins deposit into basement membrane causing disease. Like amyloid, can give extra renal manifestations.

AL amyloid: light chain forming amlyloid fibrils. Not all light chains are prone to fibrillogenesis, thus must be some form of mutation that predisposes. Look for extra renal manifestations as well. Requires tissue/histologic diagnosis.

Renal failure is often a poor prognostic sign and treatment is essentially aimed at reducing the production of the abnormal proteins and so is directed at the underlying myeloma. 

See this link for a review on myeloma and kidney disease by Korbet and Schwartz in 2006 in the JASN, also where the above image is from.

Probably viral....right?

Morning report today presented the case of an otherwise well patient presenting with fever, dyspnea, cough, preceded by unilateral parotitis. 

The patient had a travel history to the middle east prior to presentation during which the symptoms developed. 


One diagnosis? Two? Occam's razor? Hickam's dictam?

DDx of parotitis:
Think about unilateral vs bilateral...although the rules often break down.

Unilateral is often due to a structural problem such as stones, or malignancy.
Stones can be massaged out and interestingly can be aided in expulsion by acidic environments ie lime or lemon juice. 

Bilateral causes (although can present unilateral)
- Infectious: mumps, viral (EBV, CMV, HIV flu, paraflu, rsv, hmpv), TB, lyme 
- Autoimmune: SLE, Sjogren's, sicca
- Inflammatory: secondary to bulimia nervosa

DDx of fever, dyspnea, cough 

Usual suspects
- Bacterial pneumonia
- Viral illnesses (see above)

but also consider if travel history consistent....

Novel influenza illnesses

MERS-CoV - Middle East Respiratory Syndrome - coronavirus
- first described in 2012
- 139 cases to date - France, Italy, Jordan, Qatar, Saudi Arabia, UK, UAE
- morality is reported anywhere from 30-50%
- details here from the CDC website

Public Health principles: isolate, personal protection, alert PHL

Back to the case....
On presentation appeared relatively well, but did require oxygen. NP swab was negative (including negative for MERS-CoV)...however bronchoscopy was positive for RSV.

In a retrospective cohort study by Bogoch et. al in 2013, they found that 6.9% of cases will have a negative NP swab, but will be positive on bronchoscopy.
See here for the article

A word on RSV:

Not just a pediatric virus, can infect adults.
While most people will recover outside of hospital, those that require admission can be very sick and people can die from RSV. Only to highlight to take this seriously.
NP swabs may be negative as the virus may have had contiguous spread to the lower tract.

Falsey et. al in 2005 published in the NEJM results of a prospective cohort study evaluating respiratory illnesses in the elderly and found that RSV accounted for similar rates of infection, hospitalization, ICU requirements, mortality as compared to influenza A.

Click NEJM RSV 2005 article  to view. 

Lastly...what about the parotid gland swelling?
On further history the patient endorsed dry eyes, dry mouth, serology came back as ANA positive and anti-La positive, and so was diagnosed as having Sjogren's syndrome.

Looks like Hickam was right in this case.

Fever in the returned traveller

Today in morning report we discussed a patient referred for fever.

The patient was otherwise well with no significant past medical history, not on any medications, no allergies, non-smoker. 

The patient had just returned from a trip, travelling with friends

This is a case of fever in the returned traveller.

Things to know:

   1.     Where did you go

   2.     When were you there (date arrived/left)

   3.     What did you do?

a.     Pre-travel: vaccines, pills (malaria proph).

b.     Travel: Itinterary!

                                               i.     Purpose: VFR (Visiting friends and relatives) – increased risk                   because (perhaps) less likely to seek pretravel advice, meds,                   vaccines, they lose innate immunity

                                              ii.     Urban vs rural

                                             iii.     Water: fresh/salt:

                   -   Fresh water fast moving – Lepto

                   -   Fresh water slow moving - schisto

                                             iv.     Bites

            a.     Mosquitos: malaria (Anopheles- night biters), dengue                     (Aedes- day biters), yellow fever

b.     Tic: ricketsial, lyme

c.     Sandfly (leishmaniasisi)

d.     Others include: mites, fleas (plague)

     v.   Exposures:

a.     Human: sexual

b.     Dogs/bats: rabies

c.     Other animals: goats, rodents

d.     Food: bottled water? Local

                                                                 -      Diarrheal bugs (salmonella typhi), hep A, unprocessed cheese (brucella)

   4.     Illness itself

-       Associated Symptoms

o   Retro-orbital pain: think dengue (+/- rash few days later)

o   Conjunctivitis: think leishmaniasis

o   Hematuria: think schisto

o   Resolving fever followed by terrible arthritis: Chikungunya (means “leaning forward”, because bent over with pain)

o   Rose spots, relative brady, diarrhea (sometimes constipation in adults) think typhoid

Our case:

Onset of fever 1 day before returning home. Generally unwell. Headache. 3 days later rash developed.

7 days abroad.  Water sports ie scuba. No fresh water exposure. No animal exposures. No sexual activity. Pre-travel received vaccinations for hepatitis A, yellow fever.

Diagnostic approach to FTR (Fever in the Returned Traveller): 

related infection vs unrelated infection vs not infection (ie VTE, drug fever)

Think about long incubation that may have been acquired prior to leaving OR short incubation that was acquired during trip

Influenza: short incubation period 12-48 hours

Hep A, B, C, HIV, longer incubation periods

Infections related to travel

**FTR is always malaria until proven otherwise: ie that you determine that malaria is not endemic in that area or 3x thick/thin smears negative. 

(malaria, typhoid, dengue, hep A account for ~80% of diseases from tropics)

Given the constellation of symptoms, the diagnosis here was Dengue.

Dengue

-       most common mosquito borne illness

-       SA/Caribbean, SE asia

-       Aedes mosquito (day biters)

-       Urban

-       4 types 1,2,3,4

-       Once get one type of dengue will be immune. BUT if you get dengue with a second type,       higher (though still small) chance of bad complications

-       Retroorbital pain, bone pain are classic features, rash

-       Dengue hemorrhagic fever: low plt, plasma leakage

-       Measles mimics

-       Incubation time is ~7 days (often 3-4d)…after 14 days can feel like out of the woods.

-       Supportive management

   For more on FTR see this NEJM review article

Invasive pneumococcal disease

In today’s morning report, we discussed a 72 year old female presenting with fever, cough, and headache.

PMH was significant for recurrent ovarian cancer with prior debulking, radiation therapy, and multiple courses of chemotherapy, and a Port-A-Cath in place, most recent chemo 6 weeks ago for disease recurrence. She also has a history of (truly) recurrent UTI, in part due to mass compression requiring a ureteric stent.

History reveals a 5 day history of subjective fevers, productive cough, and tension headache.

Exam was normal, no evidence of CNS infection, normal respiratory exam with no oxygen requirements, no signs of IE, and a normal abdo exam, with no flank tenderness.

DDx is infection, including

-        -sinusitis

-        -pneumonia

-        -CNS infection

-        -Urinary infection (given her personal hx and RF)

     -Line infection given her Port-A-Cath

-

Some take home points;

Fever from a GU source points to pyelo.

Fever is a very sensitive sign for pyelo, over 90% sensitive

Flank pain is INSENSITIVE.

Sinusitis can be differentiated into acute vs chronic

Acute

-        -within 4 weeks

-        -within first 7 days, 98% viral

-        -Risk of bacterial goes up after day 7

           o   S. pneumo, H. inf, moraxella

Aside: The American Academy of Family Medicine recommends (as part of the choosing wisely campaign) against empiric antibiotic therapy in patients presenting with mild to moderate sinusitis lasting less than 7-days from the start of their illness

Chronic

-       - 6 or more weeks

-        -structural abnormality

Complications of acute bacterial sinusitis are rare, but are important to consider and can be thought of as intracranial (subdural empyema, epidural abscess, brain abscess, venous sinus thrombosis, meningitis) or extracranial (orbital cellulitis, orbital abscess and subperisoteal abscess). 

Back to the case…admitted for further workup, blood cultures grew 2/2 S. pneumo. 

*Given the presence of positive cultures from a sterile site, she is considered to have invasive pneumococcal disease

S. pneumo sensitive to Penicillin for both CNS or non-CNS infections, essentially meaning MIC is low.
Rates of penicillin resistance are rising, 3rd generation cephalosporins would then be the next choice.

Strep pneumo

-        -Gram positive cocci in pairs/chains, alpha hemolytic, ENCAPSULATED

-        -Other encapsulated organisms:

      o   H.inf (Type B)

      o   Neisseria

      o   GBS

      o   Klebsiella

            o   Capnocytophagia

Clinical manifestations of S.pneumo

-        -colonized in URTI: can lead to OM, sinusitis, pneumonia,

-        -this can lead to bacteremia, CNS infection, IE, MSK (Vertebral OM)

     

     See here for more on invasive pneumococcal disease