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Unpacking the Differential

November 10, 2018

Hi everyone:

In the spirit of promoting pristine clinical reasoning, I present the following case:

The Case

CC: A 66-year-old homeless man with a history of smoking and a left hilar mass presented with 3 days of chills, fever, chest pain, shortness of breath, and bloody sputum.

HPI: The patient was in his usual state of health until 6 months prior to admission when he developed a non-productive cough. After three weeks of persistent symptoms, he presented to an urgent care clinic where a CXR revealed a 4 x 4 cm2 left hilar mass. He was referred to a pulmonologist but was lost to follow up. Three days prior to admission, he developed chills, fever, and left-sided chest pain, which was exacerbated by coughing and inspiration. He had yellow sputum mixed with blood and shortness of breath with minimal exertion. He presented to the ER, where his workup was significant for a temperature of 103.4oF and an SpO2 of 85% on RA, which increased to 93% on 2L of oxygen. He had abnormal breath sounds on the left and a CXR showed a left hilar mass, volume loss, and a LLL infiltrate. He was started on ampicillin-sulbactam and admitted to Medicine.


Meds: None


-60 pack-year smoking history, currently 1ppd


-Lives on the New Haven Green

-No consistent source of medical care (last went to the VA >10 years ago)

-Served in the marines, saw combat in Vietnam

ROS: 30 pound weight loss, anorexia over the past year; voice hoarse for four months; otherwise negative in detail


-VS: Temp 102.2oF, P 84, RR 18, BP 124/76, SpO2 93% on 2L

-General: Disheveled man looking older than his stated age, breathing comfortably

-HEENT: Bitemporal wasting, trachea midline, voice hoarse, teeth in disrepair but without abscesses

-LAN: Hard, fixed, enlarged left-sided supraclavicular LNs

-Heart: Normal S1S2 without MRG

-Chest: Normal percussion and clear to auscultation on the right; left side with dullness to percussion at the base, decreased breath sounds at the base, crackles, and egophony

-Abdomen: Soft, NT, no organomegaly

-Extremities: Digital clubbing (not noted previously by patient)


-CBC: WBC 22K with 15% bands, H/H 8/24, platelets 560K

-Chemistries unremarkable

CXR: as described (the left-sided mass has increased in size compared to 6 months previously)

Imp: In summary, this is a middle-aged man with a long smoking history and a known left hilar mass of unknown etiology, now presenting with three days of chills, fever, cough, sputum mixed with blood, and an initial workup notable for lymphadenopathy, clubbing, abnormal breath sounds on the left, leukocytosis, and imaging showing progression of the mass with signs of consolidation and volume loss.

The Differential Diagnosis

Here’s where problems often arise with muddy differentials. For example, what’s wrong with this differential diagnosis?

  1. Malignancy: Lung cancer, less likely lymphoma, metastases, etc.
  2. Pneumonia (community-acquired, post-obstructive, aspiration, etc.)

I hope you can see that two discrete issues are mixed up here- a chronic complaint (the hilar mass) and an acute one (pneumonia). It’s not that the patient may have cancer or pneumonia; he almost certainly has both.

To avoid fuzzy reasoning, and to avoid missing issues that need attention, we have to unpack the differential diagnosis into discrete issues. Some patients have multiple, non-overlapping problems, like hyperglycemia and an asthma flare. Others have acute on chronic problems, like acute CHF superimposed on underlying HF-rEF. Others have secondary complications of a primary disorder, like post-obstructive pneumonia complicating lung cancer. Vulnerable patients, like the ones we commonly see at YNHH and the VA, are particularly likely to have several problems that need unpacking, because they often go for long periods, sometimes years, without medical care.

Unpacking the differential helps us see each problem more clearly and therefore give each one appropriate attention. We begin by naming each issue—in this case, “hilar mass,” “pneumonia,” and also “hoarseness”—each of which generates a separate set of diagnostic possibilities. For the hilar mass, we can consider likely malignancies and initiate a targeted workup. For the pneumonia, we can consider the likely mechanisms and organisms involved and initiate the right treatment. Similarly, we recognize that the hoarseness requires attention. If we fail to name the discrete problems, we risk missing a central issue- for example, we may treat the pneumonia but not ask what caused him to develop pneumonia in the first place, or why he’s hoarse. Unpacking the differential allows you to see the likely sequence of events clearly: an untreated lung cancer, leading to obstruction of the LLL bronchus, leading to post-obstructive pneumonia as well as likely impingement of the left recurrent laryngeal nerve, leading to hoarseness. This would generate a straightforward problem list and plan as follows:

1. Lung mass: the gradual increase in size over several months in a patient with an extensive smoking history makes lung cancer the major concern. Epidemiologically, non-small cell is most likely, followed by small cell. Other malignancies are less likely. The left supraclavicular lymphadenopathy raises concern for Stage IV disease. Plan:

-Non-contrast chest CT

-Arrange for biopsy of the left supraclavicular lymph nodes

-Depending on the results, consult oncology

2. Pneumonia: Given the mass and volume loss, post-obstructive pneumonia is more likely than community acquired pneumonia, aspiration pneumonia, or other causes. Gram positive organisms and anaerobes are the major concern. The pneumonia may be difficult to clear if there is bronchial obstruction. Plan:

-Sputum culture


-Depending on CT findings, consider consulting interventional pulmonary for possible stent, laser, or other treatments to open the airway

-Oxygen supplementation

3. Hoarseness: Given the longstanding symptoms in the context of a left hilar mass, we are concerned about impingement on the left recurrent laryngeal nerve, leading to vocal cord paralysis. Other causes such as acute laryngitis or LPR are less likely. Plan:

-Consult ENT for laryngoscopy

I hope you agree that unpacking the differential diagnoses streamlines clinical reasoning and makes the subsequent workup and treatment more straightforward. I presented a pretty obvious case, but look out for more subtle examples that present often on our services, where the differential becomes muddy. Be especially mindful when you admit vulnerable patients, because they often have several acute and chronic problems that need your attention.

Have a great Sunday everyone, I’m leaving for a hike up East Rock, looking out for red-tailed hawks.


PS- on this Veteran’s Day, please note this op-ed on the spectacular services provided by our colleagues at the VA:

By Protecting Veterans’ Health, You May Protect Your Own

PPS- Please consider signing this petition, responding to the NRA’s assertion physicians should “stay in their lane” when it comes to speaking out against gun violence:


Mark D. Siegel, MD, FCCP, FACP

Professor of Internal Medicine

Pulmonary, Critical Care & Sleep Medicine

Program Director,

Traditional Internal Medicine Residency

Yale School of Medicine

Phone: 203-785-7113

Fax: 203-785-7030

Cell: 203-589-6387

Pager: 203-370-0167

Submitted by Mark David Siegel on November 11, 2018