Asthma Exacerbation

Today in morning report we discussed an important case of a patient presenting with an asthma exacerbation.

This is an emergency and that your history/physical/investigations and management are all going to happen almost simultaneously. And of course, get help.

Some key points to consider on:

1. History:
- Questions around severity: 
# of ICU admission, # of exacerbations, # of MD visits. 
Adherence. Beta agonist use (2 more cannisters / month is sign of severity)
Other psychosocial issues
- Questions around control:
Daytime symptoms 
Nighttime symptoms
Physical exercise 
Inhaler/rescue use 
Absence work/school 
PEF 

- Triggers: 
Infection, allergen, adherence

2. Physical Examination:
Appearance, # of word dyspnea
Vitals including a pulsus if possible
Peak Flow
Chest exam. Silent chest is a bad sign

3. Labs
ABG: beware the "normal" CO2

4. Treatment:
-Bronchodilation
MDI via spacer just as good as nebulizer (and issues around infection control)
Beta-agonists, anticholinergics (in the acute setting for anticholinergics, and especially consider if due to beta-blocker)
Remember that HR may actually get better with treatment as you improve the hypoxia and constriction.
IV magnesium in severe exacerbations
- Corticosteroids
Likely longer duration than in COPDE
- ICU
Earlier assessments important, especially if ventilation needed. 
- NIV: Considerations around non-invasive ventilation discussed, may be helpful, but be mindful of delaying needed intubation.
- Intubation: tricky, if needed should be done by experienced, skilled MD (ie Anesthesia, ICU).
- Others: Heliox discussed, still probably needs more evidence.

A word on Peak Flows:
Important. Don't forget to do them. Will help to guide treatment response and disposition.
Pre-treatment of less than 25 percent personal best or less than 100 L / min should be admitted
200-300 L/min consider admission. more than 300 consider home
(These are only guidelines and need to take into consideration all other factors of the patient to best decide if admission, ICU, or home).

See this review article on management of asthma exacerbations.

Your analysis?

An inside joke entitles today's post from morning report where we actually discussed a patient who presented with a "sickle cell crisis".

Sickle cell disease results from a point mutation at position 6 of chromosome 11 leading to a glutamate to valine substitution. There are 3 main forms of SCD and these are:

HbSS- typical form of SCD

HbSC- one S genotype, and one C genotype that results from a different mutation. Less severe

HbSBeta-thal- one S and one beta thal trait.

Others include HbE, HbD, Hb Lepore.

Clinical manifestations are broad in SCD and include vaso-occlusive crises (VOC) that result from sickled RBCs obstructing capillaries resulting in ischemia and necrosis. VOC include bony pain crises, and include one of the most severe complications of SCD which is an Acute Chest Syndrome (ACS). Other complications include priapism, stroke (cause of "stroke int the young"), painful leg ulcers, AVN, as well as aplastic crises, hemolytic crises, sequestration crises,and pulmonary hypertension, to name a few.

Principles of management include fluid rehydration, appropriate analgesia, antibiotics if indicated, plasma exchange for certain circumstances such as ACS

What about hydroxyurea (HU)?

HU increases HBF concentrations, and was shown in a landmark NEJM study in 1995 by Charache et. al to reduce morbidity by decreasing the number of painful crises from a median of 4.5 to 2.5 per year. Rates of ACS, blood transfusions also decreased, and time to painful crises also increased in the HU group. An observational follow up of 233 out of 299 of these patients 9 years later by Steinberg et. al from JAMA showed a mortality reduction of 40%. Lastly, one clue that might point to adherence, is that due to its effects, HU should cause an elevated MCV, and so certainly a low MCV might suggest non-adherence. 

What about infection?

Infection is another important consideration in patients with sickle cell disease. Patient with HbSS by adulthood will be functionally asplenic because of autoinfarcting their spleen. Thus one clue that perhaps a patient dose not have HbSS disease is if they have a history of splenectomy in their PMH. Patients with HbSbetathal can have associated splenomegaly. 

As a result of either no spleen, or no functioning spleen, patients will be at risk of infection with encapsulated organisms - S.pneumo, H.influenzae, N. meningitidis - and other Gram negatives such as E.Coli, Salmonella species, and Pseudomonas. As a result, patients should be vaccinated. See this CMAJ article that discusses optimal management of patients pre-splenectomy, the vaccine aspect applies to SCD patients. 

Other principles of management

Folic acid - due to chronic hemolysis and high requirements.

Medic alert bracelet

Patient education

Click here for the original 1995 NEJM article and also here for a 2008 NEJM review on HU and SCD

Pulmonary Hypertension 

In morning report today we discussed the case of an elderly patient who presents with dyspnea. Specific points include an echocardiogram that showed a normal LV, with no significant diastolic dysfunction, but reported a very elevated RVSP (over 100). 

Given the absence of obvious left sided heart disease as the cause and suggestions of high right sided pressures, the diagnosis of pulmonary hypertension was raised. 

Approach to pulmonary hypertension

An anatomical approach is useful and from this come the 5 major categories of disease.

1. PAH (pulmonary  artery hypertension)

-idiopathic, hereditary ((bmpr2, alk (alk mutations, not the ones that cause cancer, can lead to PAH, and HHT))

-secondary to CTD (scleroderma more often CREST, anticentromere…whereas anti-scl70 is systemic, causes ILD), HIV, 

-hemoglobinopathies (ie sickle cell, anything with hemolysis leads to binding of NO that prevents vasodilation), drugs (amphetamines, cocaine, fen-phen)

1 prime: PVOD (pulmonary veno-occlusive disease)

PVOD vs PAH: one defining feature is that if PVOD receives PAH treatment, they will get significantly worse.

2. Cardiac: CHF, LV dysfunction, AS, MR, diastolic

3. Lung disease: Chronic hypoxemia eg COPD, OSA, hypoventilation syndrome or parenchymal lung disease eg ILD

4. CTEPH: treated with endarterectomy (surgery)

5. Miscellaneous: sarcoid, langerhan’s, splenectomy, mpd, glycogen storage diseases

Workup

History, physical 

-looking for consequences of and causes of pulmonary hypertension:

O/E

-Elevated JVP, CV, loud P2, palpable P2, RV heave, SOA, pulsatile liver.

PFT’s (also 6 minute walk test for prognostication, not diagnostic)

- looking for lung disease

- normal pft but isolated dlco would be hint to IPAH

ECHO

-Normal RVSP is 35

-RV dilatation, RV hypokinesis, pericard effusion

V/Q scan

-looking for CTEPH

-CT is good for acute, but not chronic. If V/Q positive, CT normal, then think of CTEPH

High res CT with contrast

-for parenchymal lung disease. Contrast is to help look for PE’s

Sleep study

BW: 

-CTD, HIV, Hgb electrophoresis etc.

Right heart catheterization

-mPAP > 25 with PCWP < 15

-Trans pulm grad is mPAP – PCWP  If > 12 then abnormal

Treatment considerations include:

- Oxygen 

- Diuretics 

- Anticoagulation (controversial)

Condition specific treatments include: 

For CTEPH: endarterectomy, Riociguat (recent NEJM link is here)

PAH: endothelin antagonist such as bosentan, vasodilators such as PDE5 inhibitors, IV epoprostenol

Lastly is transplant.

For more check out this BMJ review article on pulmonary hypertension, also where the above figure comes from.

A rash diagnosis

Morning report discussed a case of a patient who presented with non specific symptoms such as nausea, vomiting, subjective fevers, and back pain.

Based on this, proposed diagnoses based on symptom/syndrome recognition included pyelonephritis, vertebral osteomyelitis, epidural abscess. 

If the patient was delirious, how would your consideration change?
Perhaps age factors into this and would be appropriate if this were a patient who was elderly with vascular injury in the past. 

Delirium might invoke CNS infections, or may be secondary to the primary process. 

Physical examination revealed a vesicular rash, in a dermatomal distribution. 

These lesions were de-roofed and sent for analysis, which came back as VZV.

VZV:

Primary infection with VZV = Chicken Pox. Latency develops in dorsal nerve roots.

Reactivation then occurs: 

-Can be with rash = shingles, dermatomal distribution

-Can be without rash = zoster sine herpete

-Reactivation can present with or without visceral involvement eg. pancreatitis, hepatitis

Age is the biggest risk factor on a population basis for reactivation.

Neurologic complications of VZV include:

-         Zoster opthalmicus

-         Bell’s Palsy

-         Ramsay Hunt

-         Immunocompetent: can develop

o       Transverse myelitis

o       Granulomatous angiitis – can present as stroke

-         Immunocompromised:

o       Transverse myelitis

o       Small vessel vasculopathy – present as encephalitis

-         POST HERPETIC NEURALGIA

o       Post herpetic neuralgia defined as pain > 90 days after onset of rash. Age again  is RF.

Zoster associated pain comprises phase of acute neuritis and post herpetic neuralagia

 Antivirals

-         Acyclovir, Famcyclovir, Valcyclovir. (FCV,VCV may be considered over ACV because of activity, dosing)

-         Decrease rash by 0.5 day, decrease fever by 0.5 day, decrease acute neuritis phase

-         Treatment should be within 72 hours of rash. Exceptions include zoster opthalmicus, immunocompromised, one could argue for Bell's Palsy.

Post Herpetic Neuralgia treatment

-         gabapentin, TCA’s...no clear direction over which to choose, which is better. Acetaminophen, NSAIDs may help.

Other points in management include getting an ophtho assessment if V1 is involved. The role of steroids is controversial.

Zostavax

-         Indicated for greater than 60 yo

-         50% reduction in shingles

-         67% reduction in zoster associated pain

-         Similar results greater than 50 yo

-         Cannot give if on immunosupression. Should wait at least 6 months

-         Not clear when to give after acute zoster infection…

For more details see this NEJM review article on Zoster

...and this NEJM article on neurologic complications of Zoster

Complications of Alcohol

Today in morning report we discussed a patient presenting with worsening peripheral edema and ascites. 

This patient has a known history of cirrhosis secondary to alcohol.

It is important when assessing patients to have a framework of the likely causes for why they are presenting today, as well as to consider all of the dangerous complications/consequences of their underlying condition that often plays a role in their presentation. This will also help to shape your history/ddx/communications of the case.

In a patient with cirrhosis, some issues to consider when assessing:

1. Encephalopathy, also remember, think about what has caused their encephalopathy
2. SBP (Spontaneous bacterial peritonitis)
3. GI bleeds, specifically variceal bleeds.
4. Hyponatremia and neurologic sequelae from that.

Back to this patient. When assessed, there was no neurologic symptoms, mental status was normal, no evidence of asterixis. There was no abdominal tenderness, no fevers/chills/sweats. Lastly there was no evidence of melena stools or hematemesis. 

Because of his change in clinical status, the question of SBP was raised, and so a diagnostic tap was performed. 

A word on SBP:

Changes in clinical status in a patient with cirrhosis essentially warrants a diagnostic tap to ensure that they have not developed SBP. remember that SBP is mono-microbial due to transient bacteremia returning and seeding the ascitic fluid. It is not as previously thought due to GI translocation (if it were, would see polymicrobial infections). 

When doing your diagnostic tap, keep the number 250 in your head, which is the cut off of neutrophils below which is sensitive to rule out SBP.

If SBP is suspected, empiric treatment is targeted and enteric organisms and is often a 3rd generation cephalosporin. Additionally, for the treatment of SBP we will use albumin (in the absence of any other contraindications). In 1999 a study in the NEJM looked at ~65 patients in each arm of either cefotaxime or cefotaxime + albumin. Rates of renal impairment, and mortality were approximately 30% in the cefotaxime only arm compared to 10% in the cefotaxime + albumin arm. This gives an ARR of 20% and so a NNT of 5!! Granted was a small study, and the patient population needs to be assessed for whether it applies to your patient. However, this is an oft cited trial to support the use of albumin in SBP.

Last word on the neurologic complications of alcohol:

Acutely and most commonly is the intoxicating effects that alcohol has.
More seriously in the acute setting think about alcohol withdrawal, delirium tremens, Wernicke's. Chronically peripheral neuropathy, midline cerebellar disease, and rarely the marchiafava-bignami syndrome which is disease of the corpus callosum. 


See the 1999 NEJM SBP Albumin trial here

The definition is in the name.

Morning report discussed a case of a patient who was initially admitted for mild volume overload that was treated appropriately in the standard fashion, but while in hospital, abnormalities were noted on the patient's laboratory investigations...

They included:

1. Rising creatinine

2. Rising phsophate

3. Dropping Calcium

4. Very elevated uric acid

Context helps, and the further information revealed that this patient has a history of a hematologic malignancy, that has been treated with aggressive, multi-modal chemotherapy, and unfortunately has recurred with signficant tumour burden.

Diagnosis......Tumour Lysis Syndrome.

Tumour Lysis Syndrome (TLS) is aptly named, and helps to understand the basic pathophys.

Tumour cells breakdown and release their intracellular contents, specifically K, UA, PO4, and as a result of the high PO4, binds and lowers Ca.

Thus there are laboratory criteria for TLS, essentially being:

1. Hyperkalemia

2. Hyperuricemia

3. Hyperphosphatemia

4. Hypocalcemia.

Clinical criteria, are essentially all the downstream problems that the above can cause, with the big categories being:

1. AKI (think about calcium, UA, possibly xanthine precipitation)

2. Cardiac (dysrhytmias from K and Ca abnormalities)

3. Neuro (tetany, seizures)

TLS also can lead to a general inflammatory "SIRS" like reaction that can contribute to multi-organ failure.

Risk Factors for TLS include

1. Type of cancer (usually hematologic, rapidly progressive, but now noticing in other cancers previously thought to be rare).

2. Tumour burden (ie mets, bulk).

3. Treatment factors: highly aggressive, rapid cell turnover treatment 

4. Patient factors: do they have underlying kidney disease, hypovolemia, etc.?

5. MD factors: did we prophylax, give fluids

Priniciples of management:

1. Fluids, fluids, fluids

2. Excretion: whether through agents such as rasburicase (that facilitate excretion by converting UA to allantoin. Remember that allopurinol only inhibits formation of more UA, but does not mediate excretion.

Diuretics can be used. Dialysis often considered in severe cases. 

See this 2011 review article from the NEJM for more details.

The diagnosis is stroke...

wait how old is the patient?

In morning report we discussed a patient who presented with a history of expressive aphasia and right sided weakness.

If this patient were 80 years old with atrial fibrillation not anticoagulated, or if they had multiple vascular risk factors, then it would be a common case of ischemic stroke that we encounter not infrequently.

How would your diagnostic consideration change if this patient were 20, 30 or 40 years old?

In other words, how do you approach stroke in the young?

Before we explore that, remember to be diligent with your neurologic history to clarify:
1. time course
2. characteristics
3. localization
4. associated symptoms (important, and should revolve around your DDx).

This patient had difficulty speaking, remember that when assessing for a language problem, try to distinguish if there is a deficient in comprehension, repetition, naming, or fluency. Language localizes to the left perisylvian region.

The time course was over a couple days with primarily language deficits and mild weakness (later confirmed on exam). There were no obvious assoicated symptoms that we will explore in detail later.

Physical examination should be meant to help confirm/disconfirm your working diagnosis that was made from your history. Remember that the neurologic exam starts with:

1. Mental status: Language is part of the mental status exam
then:
2. Cranial Nerves
3. Motor: not just power!
4. Reflexes
5. Sensory
6. Coordination

This patient's physical exam confirmed word-finding difficulties and mild right sided weakness with no other abnormalities found on exam.

Imaging revealed a left MCA territory infarct and this patient is currently being managed and worked up to determine the etiology of the stroke.

A word on neuro-imaging (I am not a radiologist by any means, but some useful tips...in a sense radiology for dummies 101):

CT findings for stroke include: loss of grey/white matter differentiation, ribboning, sulcal effacement, MCA sign.
When looking at an MRI for stroke, one approach is first look at the FLAIR sequence...a stroke is white. Then look at the DWI (look at the 2nd or 3rd sequence), stroke should still be white...lastly look at the ADC: stroke will be black.

This patient was young, and getting back to the diagnostic approach for "Stroke in the Young".

Remember to consider the causes you normally would and so looking for vascular disease, arrythmia (atrial fibrillation) is still part of the work up.

Other etiologies and clues:

1. Arterial:
- Consider dissection, especially if there is a history of trauma, or neck manipulation, and especially if you detect a Horner's.
- Arterial embolism can result  from hypercoaguable states (thrombophilias, PV, APLA) as well as from emboli from other sources such as endocarditis.
- Consider other arteriopathies such as moya-moya 

2. Venous
- Venous sinus thrombosis can occur, especially in the setting of risk factors such as high estrogen containing OCP, and consider in a young patient with stroke complaining of headache.

3. Cardiac
- as previously mentioned endocarditis (both infectious and non- ie Libman-Sacks endocarditis in SLE)
- Cardiac anomalies, ventricular or atrial thrombi, PFO (controversial)

4. Medications
- In particular think of illicit drug use, such as stimulants that may further put at risk for hypertension, dissection.

5. Thrombophilia
- Includes myeloproliferative disorders, I also think of sickle cell here (though perhaps not a true thrombophilia), PNH, APLA, hyperhomocysteine, as well as other causes that can be investigated. 

6. Infectious causes of stroke
- Discussed endocarditis
- Also VZV, TB, Nocardia, neurocysticercosis
- Rheumatic disease, or Chagas as cause for cardioembolism.

7. Rarer things
- Genetic disorders (MELAS, CADASIL), primary vasculitis less commonly present with stroke with exception of APLA.

The differential as can be seen needs to be expanded when a "young" patient has a stroke, history and physical will still guide you to effectively investigate and manage.

See this review article in the Lancet for details.

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.