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

Weak, unwell & puffy

Morning report today was about a young patient presenting with abdominal pain, but then was found to have a history of generally feeling unwell, reportedly becoming “puffier”, gaining weight, and simply not feeling well. Physical examination included normal vitals (not what we were expecting), but significant for delayed, or “hung” reflexes, nonpitting edema throughout, as well as generalized weakness.

Ultimately, investigations revealed a TSH of > 100

Hypothyroidism ranges from subclinical hypothyroidism, overt hypothyroidism, all the way to myxedema coma.

The pathogenesis all stems from the lack of intracellular T3 and lack of conversion from T4.  This leads to cardiac dysfunction including hypothermia, bradycardia, diastolic hypertension, and if severe enough hemodynamic compromise. It also results in fluid retention and vascular impermeability which leads to hyponatremia and edema respectively. In severe cases (myxedema), CNS disturbance occurs including coma.

Remember that in severe cases ie myxedema coma, always look for a precipitating factor, which is most commonly infection, but can include cardiac events, stroke, gi bleeds, and drugs/toxins (including the rare case of bok choy induced myxedema, which is due to the thyroid inhibiting effects of metabolites of uncooked bok choy).

Clues to diagnosis on labs may include an elevated CK (hypothyroid myopathy, seen in this case as well), increased cholesterol levels and elevated liver enzymes. Also keep in mind that adrenal insufficiency can often keep the company of hypothyroidism, as do other autoimmune conditions, remembering that autoimmune thyroid disease (ie Hashimoto’s) is the most common, and part of the diagnosis is looking for these antibodies.

Treatment should be aimed at treating any underyling precipitating cause, and thyroid replacement. Remember that T3 is the active form, and that in times of systemic illness there is decreased conversion from T4 (ie the sick euthyroid syndrome characterized by normal TSH, low T3, normal T4 and elevated reverse T3).

Also remember that thyroid hormone may increase cortisol excretion and can worsen underlying adrenal insufficiency, so remember to keep an eye for that as well.

See this review article on myxedma coma for more details (the above image is from this 2011 article by Vivek et. al in the Journal of Thyroid Research).

Adrenal insufficiency

In morning report we discussed two cases from the past that highlight an important diagnosis: adrenal insufficiency.

Both case examples were that of patients presenting with fatigue, lethargy, one patient had recurrent gastrointestinal infections and both were subsequently noted to have hyperpigmentation on exam and hyponatremia, and hyperkalemia.

Subsequent testing revealed primary adrenal insufficiency...aka Addison's disease.

First described by Thomas Addison in 1855, adrenal insufficiency is an important, life threatening, but treatable condition.

                                                                                                (Bornstein, SR, NEJM 2009)

The disease is best thought of by always referring back to the hypothalamic-pituitary-adrenal axis.

Recall that CRH is released from the hypothalamus that stimulates the anterior pituitary to release ACTH, that then stimulates the production of cortisol from the adrenal glands.

Differentiate Primary (ie adrenal disease) vs Secondary/Tertiary (ie pituitary/hypothalamic disease)

Primary adrenal insufficiency is due to destruction of the gland itself, DDx includes:

- autoimmune

- infectious (TB, Fungal, HIV)

- hemorrhage (coaguloapthy, Waterhouse-Friderichson post meningococcal disease, now recognized in other infections such as Staph)

- iatrogenic (medications that inhibit the axis, surgical removal of glands)

- genetic (CAH, Adrenoleukodystorphty, Adrenomyeloneuropathy)

Secondary includes:

- tumour

- apoplexy

- ischemia (ie Sheehan's syndrome)

- infiltrative disease

Symptoms:

Non specific symptoms of fatigue, weakness, lethargy, abdominal pain, nausea.

Physical exam:

Classically described as hyperpigmentation including but not limited to the buccal mucosa and teeth, elbows, creases, nipples.

Hypotension (especially treatment refractory hypotension)

Labs:

Electrolyte abnormalities (ie hyponatremia for both primary and secondary, hyperkalemia for primary). May also see acidosis, anemia, hypoglycemia, rarely hypercalcemia, as well as eosinophilia.

Screening:

AM cortisol if < 80 sensitive to rule out, if >  ~500-550 can rule in

If AM cortisol nondiagnostic, then next step would be an ACTH aka Cosyntropin stim test.

If normal you would expect to see an appropriate rise in cortisol in response to the administered Cosyntropin.

In primary you can measure ACTH levels and would expect them to be high due to the lack of cortisol and the continued stimulation due to lack of negative feedback.

High levels of ACTH, and inappropriate response to ACTH stim test = primary AI

In secondary, ACTH levels should be low. IF prolonged secondary AI, the adrenals will have atrophied due to lack of stimulation and so above test would be abnormal. IF it is early in the course of disease, or mild, then there still may be a normal response to the standard ACTH stim test.

Further testing to diagnose secondary AI

- low dose ACTH stim test. The thinking here is that if a tiny dose of ACTH stimulates a normal response, then it is very unlikely that the patient has AI, thus it is a sensitive test

- Insulin induced hypoglycemia (should NOT be done in patients with contraindications e.g. CAD, seizures). This test induces hypoglycemia and should activate the HPA axis.

- Similarly, a metyrapone test blocks 11-deoxycortisol conversion to cortisol. This again should activate the HPA axis and 11-deoxycortisol levels should go up if there is no disease.

- Lastly one can do a CRH stim test, essentially acting as the hypothalamus to try and stimulate the pituitary. This test can help to distinguish between hypothalamic disease and pituitary disease.

Once determined if primary vs secondary, next step is imaging (adrenals for primary, head for secondary).

Other clues to secondary that may lead to earlier imaging is neurologic symptoms such as headache, visual problems.

Principles of management

- treat underlying cause

- replace cortisol, and mineralocorticoids if primary

- stress in the right situations

Remember that in primary both cortisol AND aldosterone are low because the adrenal gland itself is damaged.

In secondary, cortisol is low because of low ACTH stimulating cortisol production, but aldosterone should be normal because the renin-angiotensin system is still intact. Thus more likely to see hyperkalemia in primary.

Both primary and secondary will have hyponatremia because of low ECFV, ADH release, water retention, and in the case of primary low aldo and salt wasting.

See this 1996 NEJM review article on adrenal insufficiency

And this more recent 2009 NEJM article that touches on predisposing factors, genetics, and has more info regarding culprit meds. The above image is from this 2009 NEJM article by Bornstein, "Predisposing Factors fro Adrenal Insufficiency".

"Oh by the way, I just started taking....."

The case today in morning report had multiple issues, but one that I wanted to discuss more was that of drug reactions. 

This patient was recently treated for a presumed UTI, and is now presenting with an acute elevation in her liver enzymes and a rash.

See this previous post in regards to the approach to transaminitis

This patient's history revealed that she was seen a week prior in the ER, diagnosed as having a UTI and treated with nitrofurantoin. In retrospect, 2 days after starting this medication she developed a rash over her chest, and ultimately was found to have a rise in her liver enzymes that subsequently started to improve once her medications were held. 

To complicate matters the patient was also taking PRN ibuprofen, as well as regular standing medications of tramadol, ASA, clopidogrel, a statin, and ezetimibe. 

Always consider the medications... whether prescribed, OTC, other sources. Careful history with precise timing is key to understanding IF a drug is the cause, and if so, which one. When considering a drug reaction, it is useful to carefully plot out the course of meds and the onset of symptoms/signs.

Remember that a simple exanthem is differentiated by a complex exanthem based on whether or not there is systemic organ involvement. Fever and elevation in liver enzymes are classic associated elements. (Impossible to know if fever played a role due to her antipyretic use).

Often, with multiple medications, it may be difficult to know exactly which is implicated, and often we simply don't know. If medications are ever reintroduced, remember (if possible) to do so one at a time to monitor for a reaction.

This case continues to be one in progress, but time will tell if this is all related to a drug reaction, or if other processes are at play.

See this nice review article from the perspective of a clinical pharmacist on drug induced rashes.

Also, a drug we do not often use...tramadol. See this CMAJ 5 things to know about tramadol article.

Fever and Back Pain

The case is that of a patient presenting with back pain and fever. 

As with every case in medicine, it is important to keep your thinking broad initially and based on the gathered data, to narrow your focus. 

Further history revaled that this patient had a 3 week history of lower back pain, increasing in severity and persistence. He is a known IVDU and had been using up until 2 weeks ago. He also had associated fevers and sweats, but no other localizing symptoms of infection or other system specific complaints.

Sidenote:

There are certain bacteria associated with what is mixed with IV drugs:

- Toilet water is associated with enteric gram negative bacilli

- Lime juice is associated with candida

On exam, he was febrile, but hemodynamically stable. His exam was significant for poor dentition with perigingival erythema. His MSK examination did NOT have any point tenderness over his spine.  The remainder of his physical exam was normal including no signs of systemic diseases/syndromes.

At this point, the differential for his back pain and fever included:

Infectious

- Vertebral Osteomyelitis

- Paravertebral/epidural abscess

- Pyelonephritis

- Intraabdominal infection with referred pain

Non-infectious

- Pancreatitis

- Malignancy ie bony mets, plasmacytoma, etc.

- Connective Tissue Disease

- Mechanical back pain

- Disc disease

MRI revealed L4-5 Vertebral Ostseomyelitis. Blood cultures were persistently positive for MSSA. ECHO is pending.

Dx: Vertebral Osteomyelitis secondary to MSSA bacteremia, presumed secondary to IVDU.

A word on Vertebral OM aka Discitis

Origin
- Hematogenous spread

- Direct inoculation (ie from surgery, trauma)

- Contiguous spread

Presentation

- Back pain is most sensitive, although may not have point tenderness. Severe point tenderness may suggest an abscess.

- Fever often not present (50-60%)...may also be because of use of analgesics/antipyretics

Micro

- Bacterial: Staph Aureus, E. coli, Salmonella (e.g asplenic patients at risk of encapsulated organisms), and others, all have a 'tropism' for bone. In men with GU infection, gram negatives are often implicated as the bladder venous plexus drains to the level of the spine. CNST and P.acnes should be considered if prosthetic/fixation devices present.

- Mycobacterial ie TB Pott's disease

- Fungal infections specifically dimorphic fungi

MRSA risk factors include: homeless, incarceration, previous MRSA, contact sports, hospitalization

Principles of management 

- Get micro either from blood or biopsy or abscess drain if needed.

- Unless patient is unstable, try to hold off on antibiotics until a bug is identified.

- Duration varies, but often will be 6 weeks

- Clinical follow up is required. CRP, MRI may be useful in the right context. 

Click here for a great review from the NEJM (The above image is from this NEJM article by Zimmerli W. N Engl J Med 2010;362:1022-1029).

Polyarthritis & Fever

Today was a case of polyarthritis & fever.

The pattern, timing, and associated symptoms of the polyarthritis will be key in narrowing the differential which includes:

- Rheumatologic conditions, specifically

Seropositive conditions: RA, MCTD, SLE, DM/PM

Seronegative condtions: AS, Reactive Arthritis (1st described in 1916 after Shigella dysentery in German officers), Psoriatic arthritis (often rash will appear after arthritis), and enteric arthritis

Systemic vasculitis

Crystal disease

- Infectious causes

Bacterial: Staph aureus, Group G strep, Neisserial infections

Tick borne disease ie Lyme disease (Borrelia burgdorferi)

Viral: Rubella, Parvo, HIV

- Drug related 

Serum sickness

This patient has a history of CAD, CHF, hypertension, hyperlipidemia, a. fib, gout, CKD, T2DM. He was on ASA, warfarin, bisoprolol, candesartan, glicliazide, lasix, and colchicine.

Gout can be precipitated by certain medications that cause hyperuricemia...think "CAN'T LEAP"

Cyclosporine

ASA

Nicotinic Acid

Thiazide

Lasix

Ethambutol 

Alcohol

Pyrazinamide

Remember that the ARB losartan actually has uricemic acid lowering properties.

Physical exam revealed symmetric painful and effusive joint disease affecting the shoulders, wrists, MCPs, PIPs, no DIP involvement, knees, and ankles.

Remember that 1st MCP and DIPs often in OA, 2nd MCP think of hemochromatosis, and wrist, MCP, PIP, knees, MTP's are the 5 most commonly affected joints in RA

Given the symmetric polyarthritis RA was considered the leading diagnosis. However, he did have proximal muscle weakness, which is not in keeping with RA, and raised the question of DM/PM or MCTD.

The diagnostic criteria for RA 4 out of 7 of the following, the first 4 greater than 6 weeks

1. Morning stiffness > 1 hour             5. RF positive

2. Arthritis 3 or more                        6. Rheumatoid nodules

3. Symmetric                                    7. Periarticular erosions 

4. Hand arthritis

At this time, diagnostic investigations are still pending.

Hopefully this provides an example and overview of polyarthritis and fever with some clinical pearls along the way.

Check out this review article on polyarthritis and fever from the NEJM. It is from 1994; however, it still provides a very nice general overview. Do keep in mind that certain aspects have since been updated.

The Terrible Lymphoma

Today in morning report we discussed a young patient who presented with pre-syncope.
The patient was otherwise well, but as part of the workup had a CXR that revealed an anterior mediastinal mass.

DDx of anterior mediastinal mass, 
brought to you by the letter "T"

Thymoma
Teratoma
Thyroid
Terrible Lymphoma
...and if lung parenchymal involvment, think of lung cancer

CT confirmed the mass with neck and supraclavicular lymphadenopathy.
No other involvement. 

Core biopsies were done and pathology showed Reed-Sternberg cells pathognomic for Hodgkin's Lymphoma. Remember an FNA is not enough, need core or excisional biopsy.

Staging was Stage IIA as per the Ann Arbor Staging:
I: one lymph node group
II: > one, same side of diaphragm
III: both sides of diaphragm
IV: extranodal involvement eg. bone marrow

All patients with lymphoma should be checked for HIV, Hep B and Hep C.


Hodgkin's Lymphoma is curable, has a bimodal age distribtuion.

Treatment regimens include ABVD chemotherapy, radiation for limited stage.

From an internist's perspective, important to know the cardiotoxicity of adriamycin, with cumulative dose being the biggest risk factor. This patient had a MUGA scan prior to starting therapy.

Also, bleiomycin can cause pulmonary fibrosis, and we discussed the interesting point that for some patient groups e.g. professional athletes, perhaps this side effect may dissuade them from including in their treatment regimen (famous examples in the past).

Fertility issues also need to be addressed prior to treatment.

Click here for a review on Hodgkin's Lymphoma from the Lancet.

ACS, risk stratification, and coronary CT angiography

We had a cardiology subspeciatly morning report today where we discussed an elderly patient presenting with a classical history for unstable angina. 

This patient twice had bypass surgery, and multiple PCI subsequent who now presents with worsening retrosternal chest pain both at rest and with minimal exertion increasing in intensity and duration with diminishing relief with nitro.

Investigations revealed no new ECG changes and serial troponins were negative; however given how 'good' the story was for ischemic heart disease, the patient was admitted and treated as ACS with consultation to cardiology for further management. 

In this particular case the patient stabilized in hospital with a plan to arrange angiography for potential symptom relief in the near future. 

This case though classic, raised a couple very interesting points.

To cath or not to cath:

This patient has obvious risk factors for coronary disease and a convincing history as such. However the point was raised as to how one would know (in the absence of potentially localizing ECG changes) where the target lesion was? Given his history of bypass and multiple PCI's, it is possible that he has multiple areas of potentially significant occlusion, but which exactly is the target would be difficult to know.

One strategy to address this would be to arrange a nuclear scan or stress ECHO prior to the angiography, with hopes of localizing the target area.

What about for less obvious cases?

We then discussed patients at lower risk for ischemic heart disease and to what extent they should be worked up.

Specifically we discussed coronary CT angiography (CCTA). There are multiple studies looking at CCTA including the Rule Out Myocardial Infarction Using Computer Assisted Tomography II (ROMICAT-II) from the NEJM in 2012. This study randomly assigned 1000 patients presenting with chest pain to either CCTA or standard evaluation (which may not have been any testing) and found that time from presentation in the ER to discharge was shortened with only slightly higher incurred costs. The downside was the increased radiation exposure from the CT. 

This study along with others support that CCTA is a useful rule out test in patient with low-intermediate risk for acs, though at the cost of radiation exposure (though now with better technology the amount radiation is lowering).

One important question, is whether any further testing is required at all for low-intermediate risk patients. One could argue that in these patients, given their low risk profile, that they could be safely discharged without any further testing.  These factors and more need to be considered when weighing the risk/benefits/costs of further testing such as CCTA in evaulating this subset of patients. 

Click here for the NEJM article

Pancytopenia and Splenomegaly

Today we discussed a case of pancytopenia.

Click here for a previous blog and here for differentials of pancytopenia based on marrow cellularity.

In general, it is still a useful approach to consider causes based on the premise of decreased production, which include primary marrow disorders such as malignancy, fibrosis, storage disease, as well as myelodysplasia and aplastic anemia (congenital or acquired including viral illness parvo b19, ebv). Nutritional deficiencies such as B12 and Folate, as well as sepsis are other reasons for decreased production leading to pancytopenia.

Our patient was feeling generally unwell with persistent nausea and vomiting and constitutional symptoms. 

Physical exam was significant for splenomegaly.

CT imaging showed mediastinal adenopathy, and confirmed the presence of an enlarged spleen.

Sidenote:

The causes of massive splenomegaly (spleen >1000 g):

• infectious: visceral leishmaniasis (kala-azar), malaria
• myeloproliferative: CML, myelofibrosis
• malignancy: primary lymphoma of spleen

Bone marrow aspiration was unsuccessful; however peripheral blood film showed atypical lymphocytes, and flow was consistent with a B cell lymphoma. 

The patient will be followed up as an outpatient to facilitate formal tissue diagnosis, staging and subsequent management. 

Quick word on hematologic malignancies:

Lymphomas are classically subdivided based on Hodgkin's and Non-hodgkin's lymphoma. 

Within NHL, most helpful to think of in terms of indolent (e.g. follicular, marginal zone, mantle cell) and aggressive (e.g. DLBCL), and very aggressive (e.g. Burkitt's lymphoma)

As a general principle, indolent lymphomas are not curable, but slow growing, and aggressive lymphomas are curable, but as the name implies, more aggressive.

Treatment will likely consist of chemotherapy and steroids. Because the patient will be immunosuppressed, the last point of the day was to remember to consider latent infections and so to screen for:
- TB
- Hepatitis B
- HIV
(- Strongyloides which can in the face of immunosuppresion can lead to disseminated hyperinfection)

Renal failure in prostate cancer

Quick post today - we discussed a case of a an elderly male with metastatic prostate cancer refractory to treatment who presents with an acute rise in creatinine 1118 from a baseline of 70. Given his history of prostate cancer urinary obstruction either at the level of the prostatic urethra, or higher at the level of the ureter, potentially from retroperitoneal masses, was the leading diagnoses. Foley catheter insertion yielded less than 50 cc of urine.
Physical examination was significant for a large palpable, firm abdominal mass spanning his upper abdomen. He also had asterixis and decreased LOC. Imaging showed a 15x20x20 cm retroperitoneal mass causing bilateral hydronephrosis. He was treated with nephrostomy tubes.

Always be aware of post-obstructive diuresis, that can occur after relief of obstruction. Often this is an appopriate diuresis as retained urea is expelled causing an osmotic diuresis, as well excess salt and water from the obstruction is also diuresed. However, this can persist leading to hypovolemia. Monitor urine lytes and replace urinary losses.

The question raised was whether he require bilateral or unilateral nephrostomy tubes to relieve his obstruction. There is little evidence to guide therapy of post renal obstruction in metastatic prostate cancer. In 2009, Nariculam et. al published a study in The British Journal of Radiology where they looked at 25 patients with metastatic prostate cancer presenting with acute renal failure from obstruction. 18 underwent bilateral neprhostomy tube insertion, and 7 underwent unilateral insertion. Ultimately there was no difference in recovery of renal function and overall no difference in mortality, suggesting that survival is based on the aggressiveness of the prostate cancer rather than the insertion of one or two nephrostomy tubes. 
Multiple issues need to be balanced in practice. There is the risk of complication with tube insertion and so if one is sufficient than why insert two? However, as this study showed, some tubes can become blocked, or one kidney may have sustained significant injury and not recover function and if kidney function fails to improve after one insertion, then the patient may require a second insertion anyways.

The article can be found here

For a recap of AKI see my post from July here

Sidenote, interesting examples of uremic frost:
One from the CMAJ and another from the NEJM

Uremic frost occurs in advanced renal failure with deposition of urea and other nitrogenous waste products that crystallize on the skin. First described by Hirschsprung in 1865