April 20th - MHH - Fever in the MICU

At morning report a case was presented of a patient that developed mucormycosis after being in the ICU.



Here is a general overview/approach to patients that fever either in the MICU, or after being transferred out of the MICU. This may be hard to piece out, as some studies have suggested that approximately 70% of MICU admissions have a documented fever on admission, and 55%-90% of those admitted without a fever develop one sometime during their MICU stay.


Why is this important? Well, besides finding a cause - mortality seems to be affected. Studies disagree - some say that "any fever" increases mortality, and others state that only prolonged fever increases mortality. Nonetheless, causes must be investigated.


We can divide the categories into infectious and non-infectious causes. We commonly think of common infectious causes first (i.e. PNA, UTI etc) - but when this does not give an answer, we must turn to the less common infectious causes and the non-infectious causes.



Infectious Causes

Nosocomial Pneumonia - Consider in a patient with fever, new infiltrates, increased sputum production, leukocytosis and increased oxygen requirements. Have a high suspicion with a recent hospital admission on a patient on the vent.  Common pathogens implicated are Pseudomonas and Staph aureus, but instances of Stenotrophomonas and Acinetobacter are non uncommon in our ICUs. Viral causes need to be considered as well. Aspiration pneumonitis, which is usually not infectious, should also be on the differential. Perform trach cultures and then BAL if needed.

Bloodstream Infections - Staph is a common cause, as well as Gram Negatives. Consider Fungal infections (esp. Candida) with long-term indwelling catheters or immunosuppressed patients. You must think of catheter-related blood stream infections in all ICU patients. This is especially true when ANY line is present for >48 hours. If there is purulence at the site of catheter insertion, it usually needs to be removed and the cath tip sent for cultures (>15 CFU is suggestive of catheter related infection). Otherwise, you can draw blood cultures (from the catheter and from a distant peripheral site) - and check time to positivity. There are both quantitative (i.e. >5x colony counts from catheter compared to peripheral) and qualitative guidelines (time to positivity in lab is quicker from catheter than peripheral site) for diagnosis.

Urinary Tract Infections - Suspect in all patients with a Foley. Besides a positive culture, remember that you need both a positive Ua (with WBCs) to help diagnose this. This is because patients with chronic foleys can become colonized, and have positive cultures WITHOUT signs of inflammation on the urinalysis

Wound infections - Make sure to check the skin for infected decubitus ulcers and any other sites of soft tissue infection.

Clostrium Difficile Infection - Suspect with high WBC count, fever, diarrhea in a patient that has received antibiotics or chemotherapy in the weeks prior to the fever. Common antibiotics implicated are cephalosporings, clindamycin and the fluoroquinolones. In some patients fever can be the only initial manifestation of pseudomembranous colitis, so have a high index of suspicion. Send C. diff toxin x 2. If negative and diagnosis is high on the differential, flex sig can be done. Since this is such a severe infection, empiric antibiotics with metronidazole may be warranted while pending culture results.

Sinusitis - Cause of new-onset fever in about 5% of MICU patients. Suspect this in a patient that has a long-term nasogastric or nasotracheal tube. Also seen with nasal packing, facial trauma, and in patients on steroids. Most commonly present in the Maxillary sinuses. Workup with a plan-film of the sinuses and then do CT if the plain films are non-revealing or not definitive. Radiographic evidence alone does not give a definitive answer, so drainage with culture is needed. Most pathogens are Gram Negative Rods (esp pseudomonas, e coli and proteus), but Staph, Candida,  are not uncommon.

Abscess - Consider an abscess in a patient that has undergone any surgery or abdominal intervention prior to the surgery. This is not always precedent with these infections, so have a high likelihood for this if no other causes are found. Patients commonly "spike" fevers with these abscesses at about the same time daily. Imaging of the abdomen and pelvis should be considered in the workup


Endocarditis - This can occur without positive blood cultures, especially if the patient is partially treated or has a "culture-negative" cause (i.e. HACEK, psittacosis etc). Especially consider with poor dentition, prosthetic value, or IV Drug use. A TTE may be performed as the initial diagnostic test.

Other infections to consider - Does the patient have meningitis? Do they have osteomyelitis? Do they have peritonitis? Consider these infectious causes as well, even though they might be further down the list on the differential




Non-Infectious Causes

Thrombosis - DVT and PE should be considered in patients. Don't think that being on prophylaxis excludes this. Use the Well's Score and clinical predication rules to determine the possibility. Also, very extensive superficial thrombophlebitis can cause fever - so check all prior and current access sites.


Drug-Induced Fever - Can be from multiple agents. Common drugs are penicillins, cephalosporins, phenytoin, procainamide and quinidine. Usually patients with "drug" fever do not feel "feverish" but can manifest chills and myalgias. Drug rash , leukocytosis and eosinophillia can clue to in to this, but are frequently absent (less than 10-15% of cases!). This is not a common cause, but should be considered when other workup is non-revealing. You should, however consider drug fever in a patient that has relative bradycardia in relation to the temperature!!! Especially consider this with the scenario of an infectious source that is found with temperature initially improving during the admission - then recurring. Treatment is stopping the agent. Usually the fever will resolve in a few days if this is the cause. If the infection is improving, some will actually continue the antibiotics until repeat cultures are negative despite the presence of drug-induced fever. Also consider causes of hyperthermia (in prior blog) - i.e. serotonin syndrome, neuroleptic malignant syndrome and malignant hyperthermia. Consider these when commonly implicated agents are being given, or were recently administered. However, these conditions usually have other findings evident on exam or labs.

Ischemic Disease - Ischemic Bowel Disease or Ischemic Colitis Can produce fever. Not uncommonly, temperature elevations can be seen with myocardial ischemia or CVA. Related to the cardiac system - post MI pericarditis (Dressler's) can also cause low grade fevers.

CVA - Okay, just mentioned above, but should be another category. This is especially common when the posterior fossa or hypothalamus are involved. Subarachnoid hemorrages are also notorious for causing fever in the MICU. Have a high suspicion of this post-trauma, in the elderly, in alcoholics, or in patients with coagulopathy

Acalculous Cholecysitits - Think in our medical patients that are either septic, on a vent, or is getting parental nutrition. Perform U/S as first test. May actually need a CT scan If non-conclusive since HIDAAs in this setting give false positive rates >50%.

Pancreatitis - In the ICU setting, pancreatitis causes by procedures (ERCP), infections and medications should be considered. 

Acute Liver Injury - Unless there is an infectious agent present, this is usually due to ischemic causes or drugs. High transaminase levels can clue this into the cause of fever


Endocrine Diseases - Adrenal Insufficiency and Thyrotoxicosis are possible causes. Adrenal Insufficiency in the MICU is more common. Usually the adrenal insufficiency which is severe enough to cause fever is not due to primary causes (i.e. Addisons) or withdrawal of steroids - but from SIRS/Sepsis, adrenal hemorrhage with DIC or other causes, or adrenal infiltration (i.e. TB). Keep Pheochomocytomas in mind as well.

TTP/HUS - Consider this as a cause of fever especially from drug effect (TTP) or infections (HUS). Fever is usually a LATE manifestation of TTP, so be on the lookout for these conditions in the setting of thrombocytopenia or microangiopathic hemolytic anemia. It is not uncommon for MICU patients to have thrombocytopenia, so have a high suspicion and sent a blood smear to look for schistocytes.


Post-Op State/Atelectasis - Fever is not uncommon after surgery, but usually do not produce very high temperatures, and rarely last >72 hours. There is some "controversy" that atelectasis actually causes fever. Some believe that the post-operative state, which causes atelectasis, is the actual cause of fever. Still, this is up for debate...


Alcholol Withdrawal and Delerium Tremens - Consider this could be the cause of fever and a hyperdynamic state in a patient with history of significant EtOH use prior to their MICU admission. Not uncommonly seen with benzo withdrawal, and even fevers reports with opiate or barbiturate withdrawal.

Iatrogenic Causes - There are reports of fevers being reported in the MICU due to faulty equipment (i.e. heated mattresses) - this is not a common cause, but it's certainly a cost-effective element to look for. Sometimes there is a febrile response in patients post-procedure - after endoscopy, bronchoscopy or even post endotracheal suctioning. Make sure there is no reaction due to blood product administration as well.

And as always, with any differential regarding fever don't forget the vast array of rheumatic and malignant causes.


The HIV/Cancer Patient:
Although the above applies to the HIV patient (or any immunocompromised patient), some other considerations include Acute HIV Infection, Higher Suspicion for Meningitis/Encephalitis and Consideration of Typhilitis (necrotizing infection of colon) in cancer patients.


Workup:
This is an approach to workup in the article by Dimopoulos and Falagas:

Treatment


First the Obvious:
1) Find the cause and treat it specifically
2) Until a cause is found, or unless a non-infectious source is obvious - give broad-spectrum antibiotics to those patients that are unstable (which would be the norm in the MICU)


Now the controversy:
Should you just lower the temperature.  There are considerable arguments for and against the use of antipyretics.  There is no doubt that they should be used in two circumstances: When the temperature is extremely elevated (i.e >103.5 degrees) or when any fever is present in a patient where the state would be detrimental (i.e in the setting of MI or CVA). There is also some evidence in patients with needs for high FiO2, that lowering the fever decreases oxygen requirements.  Some will treat routinely to simply lower the temperature - there is evidence in the surgical ICUs that this either increases mortality or makes no difference.  Similar evidence is lacking in the MICU patients.




References -
Dimopoulos, G & Falagas, M. Approach to the Febrile Patient in the ICU. Infect Dis Clin N Am 23 (2009) 471–484


Laupland, K. Fever in the critically ill medical patient. Crit Care Med. 2009; 37[Suppl.]:S273–S278


Marino, P. The ICU Book. Lipincott Williams and Wilkins. 2007

Riga, M et al.  Rhinosinusitis in the intensive care unit patients: A review of the possible underlying mechanisms and proposals for the investigation of their potential role in functional treatment interventions.  Journal of Critical Care (2010) 25, 171.e9–171.e14

Rizoli, S & Marshall, J. Saturday night fever: finding and controlling the source of sepsis in critical illness. Lancet Infectious Diseases 2001; 2: 137–44

April 15th - MHH - NMS and Hyperthermia

What follows is a quick overview of hyperthermia (most of which comes from my intern lecture on fevers)


What is Hyperthermia?


As opposed to Fever, Hyperthermia is an increase in temperature over the body’s thermoregulatory set-point. This occurs when body metabolic heat production or environmental heat load exceeds normal heat loss capacity or when there is impaired heat loss.

 NOTE: These patients usually will have temperature elevations above 102 degrees




Causes of Hyperthermia:
Heat Stroke: Exertional vs. Non-Exertional
Heat Exhaustion
Thyrotoxicosis
Drug Induced (i.e. malignant hypertension, neuroleptic malignant syndrome, serotonin syndrome)
Pheochromocytoma
Central Hyperthermia/Dysregulation (post trauma/CVA)


Some more details related to the drug-induced causes:

Neuroleptic Malignant Syndrome
Background: Seen in about 0.2 percent of patients who receive neuroleptic agents (common ones include haloperidol and chlorpromazine), usually within the first 30 days of therapy. Other drugs implicated include Phenergan and Reglan. Can be seen in patients that rapidly decrease dose of L-Dopa. 


Findings:  Over a period of 24 to 72 hours there may be symptoms of muscle rigidity, extrapyramidal abnormalities, altered consciousness, and autonomic dysfunction (labile blood pressure, diaphoresis, tachyarrhythmias, and incontinence).  Laboratory findings include hemoconcentration with leukocytosis and hypernatremia, acidosis and electrolyte disturbances, rhabdomyolysis, and abnormal renal and hepatic function.


I memember learning this for the USMLE exams to help remember some of the findings with NMS:
F—Fever
E—Encephalopathy
V—Vitals unstable
E—Elevated enzymes (elevated CPK)
R—Rigidity of muscles


Treatment:  Stop the offending medication and use cooling blankets.  Patients will likely need aggressive volume replacement.  Some studies show decreased mortality rate when bromocriptine or amantadine are administered. Dantrolene can be given, but studies show conflicting views regarding efficacy. 


Serotonin Syndrome:
Causes:  Many drugs/combination implicated: These include MAOIs, TCAS, SSRIs, opiates, cough medicines, weight-reduction agents, antiemetics, antimigraine agents, drugs of abuse.


Findings: Fever, Tachycardia, Hypertension with Mydriasis/diaphoresis. LE Myoclonus, Tremor, increased BS/diarrhea, agitation/AMS. This can be differentiated from neuroleptic maligant syndrome by a few findings: The presence of elevated CK, Leukocytosis or muscle rigidity are suggestive of NMS and NOT serotonin syndrome


Treament: Stop the offending agent and give supportive care (including benzos for agitation). More severe cases can be treated with cyproheptadine


Malignant Hyperthermia
Halogenated inhalation agents and depolarizing muscle relaxants (i.e. succinylcholine) are most often responsible for causing this.  A positive family history of similar events is common.


Findings: High Fevers and severe muscular rigidity is characteristic: other typical findings include hypotension, tacypnea, tachycardia, arrhythmias, hypoxia, hypercapnia, lactic acidosis, hyperkalemia, rhabdomyolysis, and disseminated intravascular coagulation.


Treatment: Stop the drug, give hydration and oxygen, and start cooling measures. Dantrolene should be given as well. Note that Dantrolene should be given prior to anesthetic procedures when this may occur due to prior events or family history

April 15th - MHH - Aortic Insufficiency

Today at MHH a patient with endocarditis and severe Aortic Insufficiency was presented.  What follows is a quick board-relevant focus on Aortic Insufficiency.  One must think of the disease in the context of whether the AI is acute or chronic.












Causes:
The more common causes of Chronic Aortic Insufficiency/Regurgitation are:
Bicuspid Aortic Valve
Aortic Dissection
Infective Endocarditis
Calcific Disease of the Aorta/Myxomatous Degeneration
Marfan Syndrome
Hypertension
Rheumatic Heart Disease
Other Rheumatic Conditions (i.e. Rheumatoid Arthritis, Anklyosing Spondylitis, Reactive Arthritis)

Acute AI is usually causes by one of the following:
Infective Endocarditis
Trauma/Dissection of the Ascending Aorta


Symptoms:
Depend somewhat on whether the patient has acute or chronic Aortic Insufficiency.
Acute AI usually presents with sudden onset of pulmonary edema and dyspnea
Chronic AI usually presents with progressive symptoms of congestive heart failure. 
Also - keep in mind the symptoms associated with the cause of AI (i.e. fever with endocarditis)
Physical Exam Findings
Acute:
Patients will present with symptoms of cardiogenic shock - Tachycardia is common.  Look for Pulsus Paradoxus.  May have difference in BP between both arms due to dissection.  The murmur is a very soft  diastolic murmur at the LUSB (or it can he heard at the RUSB with aortic dissection).  The murmur is actually infrequently heard since the equilibrium of pressures occurs quickly. 


Chronic:
Patients with have a widened pulse pressure (Systolic - Diastolic < 100). S1 is soft or sometimes absent.  A Decresendo murmur at the LUSB is common (like acute, this murmur may may be at the RUSB with aortic dissection). A concurrent S3 is commonly heard. 
Multiple other Physical Exam Findings can be present due to the wide pulse pressure - Muller Sign (uvular pulsation), De Musset Sign (Head bobbing in synchrony with systole), Traube sign (Pistol Shot Femoral Murmur), Durosiez Sign (Femoral Mumur heard with compression), Corrigan Pulse (Rapid Upstoke when quick collapse), Becker's Sign (Retinal Pulsations), Quincke Pulse (capillary pulsations)


Workup:
Should include an EKG (may show Left axis and/or LVH), CXR (cardiomegaly, interstitial pulmonary edema, wide mediastinum?) and TTE.  Perform a CT or TEE if suspecting dissection. Most patients should have a serum RPR/VDRL sent.


Treatment:
Acute Aortic Insufficiency will usually need emergent valve replacement. In the meantime, IV nitroprusside or nitroglycerin can be used for preload reduction.  Lasix for volume overload.  Supportive care with dobutamine should be administered for cardiogenic shock.  DO NOT Place an intra-aortic balloon pump!


Medications (i.e. vasodilators such as ACEI, nifedipine or hydralazine) can be given to:
1- Reduce symptoms
2- Patients that have Hypertension
3- Patients with Severe AI that may be asymptomatic, but have LV dilatation


Surgery (AV Replacement) is indicated for:
1- Symptomatic patients that have severe AI regardless of LVEF
2- Asymptomatic patients with severe AI and LVEF <50%
3 -Chronic severe AR when undergoing other cardiac surgery (i.e. CABG)


Prognosis/Followup:
The most important determinant factor is LVEF.
In patients without  symptoms and normal LVEF, an echo is required every 2-3 years
In patients with symptoms or decreased LVEF, an echo is needed every 6-12 months

Image References:
www.pages.drexel.edu/~nag38/index.html

April 15th - LBJ - Sterile Pyuria

Today at LBJ the Renal Service presented patient with HIV that had with multple systemic complaints.  They were consults for AKI (baseline Cr 0.9 - now 5.4) and on the Urinalysis the patient had sterile Pyuria.  Here is a quick review are the causes of sterile pyuria (Significant WBCs - meaning at least 5-8 per hpf on Urinalysis with few/no bacteria and negative Gm Stain).

Make sure the specimen is obtained appropriately (i.e. clean catch) before making the call of sterile pyuria!!!

Infectious Causes
1) Tuberculosis of the GU Tract (work up with Urinary AFB)
2) Gonnorrhea/Chlyamydia infection (Can send G/C Probe to w/up) or UTI with "other" fastidious organisms (i.e. ureaplasma)
3) Fungal Infections of the Urinary Tract
3) Reports of some Viral Infections of GU tract causing sterile pyuria
4) Recently treated UTI (of any cause) in the last 2 weeks

Inflammatory Causes
1) Prostatitis (without active infection)
2) Appendicitis or Diverticulitis (when adjacent to bladder)

Systemic Diseases
1) Lymphoma of the Bladder
2) Amyloidosis, Leukemia and Myeloma (via causing a chronic interstitial nephritis)
2) Sarcoidosis
3) Malignant hypertension (usually with concurrent hematuria)
4) Kawasaki Disease

Renal Causes
1) Renal Vein Thrombosis (Consider in a patient with nephrotic syndrome + flank pain)
2) Intersititial Nephritis (and it's various causes - Analgesic/Antibiotic/other drug induced, lupus nephritis, Sjogren's, vasculitis, treated pyelonephritis, heavy metals)
3) Renal Papillary Necrosis (can be from NSAID use, Sickle Cell Disease or even obstruction)
4) Nephrocalcinosis (suspect with RTA Type I) and chronic/recurrent nephrolithiasis
5) Cholesterol Emboli Syndrome (Consider with concurrent glomerulonephritis and recent vascular intervention)
6) Polycystic Kidney Disease
7) Interstitial cystitis

------------
References:
Dieter, R.  Sterile Pyria: A Differential Diagnosis. COMP THER. 2000;26(3)
Massry et al. Textbook of Nephrology
Fausi et al. Harrison's Principles of Internal Medicine 16th ed

April 9th - MHH - Thyrotoxicosis

Today at Morning Report a Patient with Thyrotoxicosis was presented

So what does this mean?
Hyperthyroidism is the general term for increased thyroid function
Thyrotoxicosis is sometimes used as a synoynm, but generally refers to increased circulating levels of T3/T4. 
Thyroid Storm is a serious complication, usually in untreated patients with infection/surgery/trauma and others







Causes:
Graves Disease
Toxic Multinodular Goiter
Thyroiditis
Thyroid Adenoma
Factitious
Also - Struma Ovarii, which is rare

Some physical signs/symptoms with thyrotoxicosis:
General & Vitals: Tachycardia, Fevers, Heat intolerance, Weight Loss, Anxiety, Insomnia, AMS
HEENT: Graves opthalmopathy ("foreign body sensation," periorbital edema, conjunctival injection, increased lacrimation.  Diploplia and Proptosis can be present as well
Neck: Goiter (Look for bruit in patient with Graves)
Cardiovascular: Tachycardia, Systolic Flow Murmur on Exam.  Patient may have irregular rhythm due to atrial fibrillation.  Remember that thyrotoxicosis can exacerbate/cause CHF or exacerbate CAD
Pulmonary:  Dyspnea
GI: Increased stool frequency
GU: Oligomennorhea
Neuro: Tremors and Hyperreflexia (rapid relaxation phase)
Skin: Moist and warm, palmar erythema may be present, pretibial myxedema
Nails: onycholysis

Caveat for the Elderly - There is a term called apathetic hyperthyroidism.  Instead of presenting "classically," the elderly can have a complaint of just weakness, weight loss and/or atrial fibrillation

Workup/Diagnosis
Send a Serum TSH.  A level <0.1 is consistent, and a Free T4 should then be sent.  If the T4 is normal then T3 should be measured, as there are instances of this alone.  If the TSH is low in the setting of a Normal T4 or T3 then the patient may have either "subclinical hyperthyroisism" (which would technically be a misnomer if the patient presented with the above signs/symptoms) or Sick Euthyroid Syndrome due to underlying disease.  Note in Sick euthyroid syndrome the T4 is common'y either low or normal. You can confirm this state with an elevated reverse T3.

One can order a RAIU to differentiate the causes of hyperthyroidism/toxicosis.
High RAIU States include: Graves Disease, Toxic Multinodular Goiter and Adenoma
Low RAIU States include: Thyroiditis and Factitious Causes

Usually this testing is not always needed as physical findings of Graves disease are obvious in most causes.  The presence of eye findings and/or pretibial myxedema is almost always Graves.  If the patient has either a diffusely nontender goiter OR a non-palpable thyroid usually have Graves as well

Also - workup the causes of what may have exacerbated the thyroid state - i.e. infection

A Note About Thyroid Storm
This can be caused by infection, surgery, trauma, DKA, Pregnancy
Patients will be very tachycardic (or have atrial arrythmias), fevers, N/V, tremors and AMS and can progress to a comatose state.  See below for scoring system:

Treatment for Acutely Ill/Serious Thyrotoxicosis/Storm
PTU 300mg po q6 hours
SSKI 1-2 Drops po q12 hours
Propanolol 40mg po q6hours and titrate if needed



See this link for an article from Endocrinology clinics regarding thyroid storm, with the scoring system:
http://www.scribd.com/doc/6837836/Thyrotoxicosis-and-Thyroid-Storm

April 6th - LBJ - Multiple Myeloma/Amyloid

Today at Morning Report a Case of Multiple Myeloma was Presented. Here is a brief overview of the disease and what you'll need to know for boards regarding plasma cell disorders and amyloidosis






Multiple Myeloma is the most common malignant plasma cell dyscrasia. There are many other malignant and secondary plasma cell disorders, most of which are beyond what you'll need for boards.  Also keep in mind there are various subsets of non-malignant plasma cell disorders (i.e. MGUS) which you should be aware of

Multiple Myeloma - Presenting Symptoms/Physical Exam
General - Fatigue and Weight Loss are Common
Anemia - Pallor is the most common finding on examination
Bone Pain, Osteopenia and Pathologic Fractures - From Osteoclast activity and Lytic Lesions
Renal Failure - Symptoms of azotemia from light chain deposition or calcium impairment of renal perfusion
Nephrotic Syndrome - Can present with edema, increased risk of thrombosis
Hypercalcemia - Can present as various symptoms (i.e. confusion, renal stones, constipation etc)
Recurrent Infections - Due to Immunglobulin Disease
Bleeding Tendancy - Platelet and Coagulation Dysfunction
Neurologic Complications - Radiculopathy, Cord Compression, Polyneuropathy
Leukostasis - Uncommon, but with a very high plasma cell burden - patients can get Blurred Vision/Headache/Heart Failure/Dyspnea.


Always think of Myeloma in a patient (especially elderly) with anemia, renal failure and hypercalcemia

Lab Findings/Workup/Diagnosis:
In General, to diagnose Multiple Myeloma we use the Working Group Criteria or the WHO Criteria. Although there are other lab findings that are not specific parts of the diagnostic criteria. In general, the WHO criteria are a bit more pathology based, and the Working Group is more clinically based.  I'll put both of them here so you are aware:

WHO:
The diagnosis of multiple myeloma requires a minimum of one major Criterion  + one minor criterion OR
three minor criteria with bone marrow plasma cells >10% or a monoclonal protein


Major criteria
I Plasmacytoma on tissue biopsy
II Bone marrow plasmacytosis with > 30% plasma cells
III Monoclonal globulin spike on serum electrophoresis (> 3 g/dL for IgG, > 2 g/dL for IgA) or on concentrated urine electrophoresis (> 1g/24h of k or l light chains)

Minor criteria
Bone marrow plasmacytosis 10 to 30% plasma cells
Monoclonal globulin spike less than the level defined above
Lytic bone lesions
Residual normal IgM <0.05 g/gL, IgA < 0.1g/dL, IgG < 0.6g/dL

Working Group:
1 - Monoclonal Plasma Cells in Bone Marrow >10% OR a plasmocytoma on biopsy
2 - Monoclonal Protein in serum or urine (send SPEP and UPEP with IF and Serum Light Chain Analysis)
3 - Any one of the following organ related diseases:
     Calcium Elevated, Renal Insufficiency, Anemia, Lytic Bone Lesions or Osteopenia
   
Other Lab Findings in patients with myeloma:
BUN decreased
Negative anion Gap acidosis
Proteinuria of various severity on Ua
Globulin Gap
Alk Phos is NORMAL (remember this increases with blastic disease, not lytic disease)
Send LDH and B2 Microglobulin for staging and prognosis

Treatment:
The mainstay of treatment is supportive care: 
Transfusions for severe anemia and most patients should get EPO for anemia
Dialysis for Renal Failure
Bisphosphonates for lytic lesions
Saline and bisphosphonates for hypercalcemia
Prophylactic immunizations
Monthly Immune Globulin Infusion for recurrent infections
Radiation Therapy for Plasmacytomas or refractory bone pain

Remission is rare in patients, and is usually best achieved with autologous bone marrow transplantation. However, this is usually offered to patients that are <70 years old with good performance status - and unfortunately most patients with myeloma do not fit into this category

Positive Response to treatment is seen in about half of patients that recieve various combinations of treatment - including alkylating agents, steroids, anthracyclines and thalidomide.  Chemotherapy regimens including doxorubicin and vincristine are used with treatment failure. Lenalidomide, an analog of thalidomide, has less side effects (i.e. less fatigue) but also carries the risk of thromboembolic disease.  Bortezomib is a proteasome inhibitor that has been used as well. 


Non-Malignant Plasma Cell Disorders. Most are here to be completen, but you should really know MGUS for boards:
1) Monoclonal Gammopathy of Undetermined Signficiance - Less than 10% Plasma Cells with no symptoms or systemic complications.  This is present in about 2% of patients >50 years olf.  Annually, about 2% of patients transform into Myeloma - and about 20% will get myeloma during their lifetime. So, these patients need regular SPEP and UPEPs and physical exams/visits with clinicians to look out for progression to myeloma.  BM Bx will be needed in patients with MGUS that have concerning signs/symptoms that are a change from their regular status.  MGUS is seen in the general population, but is seen with increased incidence in those with autoimmune diseases, cirrhosis, and HIV

2) Smolering Myeloma - Plasma Cells greater than 10% but less than 30% without signs/symptoms

3) Indolent Myeloma - Plasma Cells greater than 10% but less than 30% with only mild anemia or <3 lytic lesions

Waldenstrom's Macroglobulinemia
This disease is causes by increased secretion of IgM paraprotein by plasma cells (as opposed to IgA or IgG in Myeloma.)  Can present very similar to MM, but these patients are at a higher risk of getting a hyperviscosity syndrome (CHF, AMS, MI, CVA, Retinal Complaints) and organomegaly is common. Treat hyperviscosity with plasmapheresis + Chemotherapy (agents used include rituximab, chlorambucil or fludarabine)

Amyloidosis:

Think of AL Amyloidosis in a patient with any plasma cell dyscrasia that has a change in symptoms (especially CHF). There are multiple other forms of amyloid (i.e. AA and inflammatory conditions such as Familial Mediterranean Fever) 

There are multiple findings/clues for amyloid:

General: Constitutional Symptoms
Skin: Purpura around face, neck, eyelids, “Shoulder Pad Sign,” Nodules
CV: Congestive Heart Failure Symptoms, Conduction Blocks, Arrythmias
GI: Dysmotility, Obtruction, Organomegaly
Heme: Anemia, DIC, Bleeding
Nervous System: Paresthesias, syncope, changes in bowel movement, carpal tunnel
Other: Change in Voice/Macroglossia

Remember that CHF is the cause of Death in over half of patients with myeloma.  They will have a restrictive pattern of filling, and classic septal hypertrophy changes/"snowstorm" appearance of the septum:

 
Diagnosis of Amyloid: 
Biopsy of an affected site will give the best yield. So if there is renal failure you may consider renal biopsy.  This will have the highest yield, but of course risks vs benefits must be weighed.  Other less invasive ways to diagnose include: Abdominal Fat Pad or Rectal Biopsy for Congo red stain (looking for apple-green bifringence). These have a reported diagnostic yield of between 70-85%
 
 
 
 
Treatment:
Best survival with high-dose melphalan and stem cell transplant, but this is not offered to most patients

References:
Images Courtesy of:
University of Virginina Dept of Heme/Onc &
http://www.stanfordhospital.org/ - information page on AL Amyloidosis

April 6th - MHH - HIV and Shortness of Breath

Today at Morning Report a Case of Dyspnea in a Patient with HIV was discussed.  The differential for patients with HIV/AIDS presenting with dyspnea is varied, and one must add additional conditions not seen in immunocompetent patients.  Here is a general thought process to causes in these patients






Infectious Causes
Bacterial Pneumonia (i.e. "Community Acquired") is your number one thought in this category, as strept pneumoniae is the most common pathogen in HIV patients.  They are also at an increased risk of getting empyemas. If you see an effusion or consolidation, think this bug first.  Blood Cultures, Sputum Cultures and Urine Antigen can be sent, but you must think of this diagnosis clinically. 


PCP/PJP - We see this very commonly, especially in patients with CD4 Counts Less than 200. The "Classic" presentation is dyspnea on exertion, fever, scant productive cough and hypoxia that is progressive and worsened with exertion.  We all Send LDH Levels - the Sensitivity in studies ranges from about 86-97%, but the specificity hovers around 50%.  CXR can show the "batwing" appearace - but PCP can appear as any bilaterial or unilateral infiltrate.  Early in the disease, the CXR may be negative.  Sputum Cultures can be sent for diagnosis, but the sensitivity is about 40%.  In patients with suspected PCP and negative sputum cultures, bronch should be performed.  Treat with Bactrim and add Steroids is the Pa02<70 or the Aa Gradient >35.


Viral Causes - Especially CMV


Fungal Causes - Histoplasmosis and Crypto are high on the list, especially in Houston. Keep Blastomycosis in mind with Skin Lesions, and Coccidio with contact in the endemic SW region.


Tuberculosis -  Even if you are thinking PCP, sputum cultures for APB can be considered. A PPD can be placed, but doesn't tell you as much...


Atypical Mycobaterium - i.e. MAC. Have a high suspicion especially with CD4 Counts below 50, although not uncommon in counts <100.  Send Sputum Cultures.  If they stain Acid Fast Bacilli, you would usually treat for MTB untill the PCR/culture reveals an atypical organism.  Although, most would add a macrolide to the treatment regimen while awaiting final cutures, when they have a high index of suspicion of atypical mycobacterium.  


Malignancy


Lymphoma - Both NHL and Hodgkin's should be considered. In general, NHL (especially B Cell Types) are highest in these patients. Common forms include Burkitts, DLBC, and Large Immunoblastic Lymphoma.  Keep in mind, that the incidence of Hodgkin's Lymphoma is increasing in the HAART era, and is rising in patients on treatment for HIV.  The tumor burden in the lungs alone/mediastinal involvement can cause dypnea. Always consider that this may be happening with your patient as the CXR with lymphoma can easily mimic infectious causes. 


HHV-8 Associated Malignancies - Kaposi's Sarcoma involving the Lungs, Castleman's Disease (A lymphoproliferative disorder) and Primary Effusion Lymphoma


Consider other Malignancies - Think both Primary Lung Cancer and Metastatic Disease. HIV increases the risk of Primary Lung Cancer regardless of smoking, and there is evidence of increased risk of metastatic spread of other primary cancers.


Lung Disease


Interstitial Lung Disease - Nonspecific interstitial pneumonitis and lymphocytic interstitial pneumonitis are very prevalant in HIV patients. 
There is also reported evidence of increased incidence of pulmonary alveolar proteinosis and desquamative interstitial pneumonitis.


Pneumothorax - A result of PCP/PJP infection, or various other secondary causes


Pulmonary Hypertension - Remember that HIV is a cause of seconary Pulmonary HTN


Pulmomary Embolism


Cardiac Disease
Congestive Heart Failure - Especially Dilated Cardiomyopathy with HIV


Pericardial Effusion/Tamponade - HIV, Fungal, TB, Malignant Causes


Ischemic Heart Disease - There is evidence of increased risk of CAD with HIV and some interesting papers that Protease Inhibitors contribute to this


Other Causes to Consider:
Rheumatic Diseases  - i.e. Vasculitis
Drug Reaction
Anemia (Acute - bleed from carcinoma or other various causes of colitis in HIV Patients. Chronic - consider BM suppression from HIV itself or other malignant/infectious causes - although this is less likely to causes acute dyspnea)

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