The last perspective in medicine was about sudden changes.  This post is on more insidious changes and the diagnostic challenge.

Diagnostic Challenges Introduction: A Case Report

There is an interesting yet sometimes uncomfortable situation in medicine: when someone’s health is not quite right. Still, the diagnostic tests and the clinical condition have not yet materialized to allow a physician to make a diagnosis.  There is certainly a sweet spot in the timing of the diagnosis: long enough to discern one cause from another and confirm it;  not too long that a person is left with discomfort or a health risk.

A patient may come in with a nonspecific series of complaints in the inpatient setting:  fatigue, chills, jaundice. In addition, there may be nonspecific test results: elevated liver tests, a low white blood cell count, low platelets, and high bilirubin.

This very circumstance happened in a patient that I evaluated recently. This series of findings is described as a mononucleosis syndrome.    The challenge is that there are many things, infectious, rheumatologic, and neoplastic, that can cause these findings besides Epstein Barr Virus (EBV), the virus that causes “mono.”

The patient developed symptoms over a period of three weeks.  She noticed jaundice and increased fatigue.  She had no flu-like symptoms, sore throat, lymph node swelling, or sick contacts.  A battery of infectious diseases tests was performed, but none of them singled out a process.  A CT scan showed an enlarged liver and spleen.  Over a period of several days, she improved to the point that she could be discharged – without a diagnosis.

We discussed the next steps, which included a liver biopsy.  The pathology of the liver sample suggested a process that was a result of many possible causes. One proposed condition was a rare one, known as hemophagocytic lymphohistiocytosis (HLH), which is caused by autoimmune, neoplastic, or infectious causes.  No telling findings otherwise were seen.  It was like taking a step forward to nowhere. Fortunately, she was feeling better.

We discussed the results.  I brought up a strategy to address diagnostic challenges.

In medicine, seldom is a condition diagnosed on the spot.  However, it does happen. An astute physician can evoke a diagnosis like they are conjuring up magic. For example, one of my mentors in infectious diseases, while rounding with us on a particularly vexing patient, walked in the room, looked at the patient’s face and skin (he had some ulcers on his lips and a generalized rash), and almost immediately said, “he has Mycoplasma.”

And that is what he had.  All other tests were negative, but he had the typical chest X-ray finding of Mycoplasma, a cause of “walking pneumonia,” and all his tests – HIV, syphilis, etc. were otherwise negative.  We were spellbound as we reviewed this less common presentation of Mycoplasma.

A disease process sometimes takes time to present, grow, and enable a safe way to diagnose it. For example, some diseases can be diagnosed fairly reliably by looking at the skin, the body’s largest organ.  In fact, there is an app for that. This is because the skin houses a network of vessels that mirror what is going on in the entire body.  Occasionally, systemic diseases can present with skin findings, facilitating a less invasive way of making a diagnosis.  This includes conditions such as sarcoidosis, T-cell lymphoma, malignant melanoma, metastatic squamous cell carcinoma of the lung, and lupus vasculitis.

When the disease is confined to the deeper vessels and lymphatic system, the manifestations will often be nonspecific, including blood and radiologic tests.  Since many infections can present similarly, a shot-gun approach isn’t always high-yield or cost-effective.  At that point, the next step becomes a dance between watchful waiting and more aggressive, invasive testing.

The tests can only hint at the possibilities.  Sometimes, there is a need for tissue.  It reminds me of a patient I saw from Africa who presented in the US with peritoneal fluid, lymph nodes, and thickening changes of the peritoneal lining.  These changes usually occur when there is an inflammatory process.

The pathology of the peritoneal biopsy showed non-caseating granulomas, a feature of sarcoidosis but certainly not exclusive to it.  These are basically areas of scar change surrounded by white blood cells. She was from a part of Africa, where an article was published on cases of sarcoidosis.

Noncaseating Granuloma of Sarcoidosis (Ref:  Wikipedia)

It was also a high prevalence country for tuberculosis, presenting as non-caseating granulomas (though more commonly caseating changes).  Her blood test (quantiferon) was positive for tuberculosis, but it wasn’t clear if it was a latent infection (and had sarcoidosis) or peritoneal tuberculosis.  I saw her in the hospital; she was recently discharged from a different.  She had just had another peritoneal biopsy there.

I called the pathologist told him that I found it worrisome for tuberculosis.  He looked at the smears before (tuberculosis stains with acid-fast stain) and did not find anything.  My call was enough to get him to go back and look.  He called me a few hours later, saying that he found “one acid-fast bacillus.”  We started her on four drug tuberculosis, and after about one week, she had already felt better.  None of the cultures ever grew; none of the genetic tests were ever positive.  Yet, she had peritoneal tuberculosis.

Although ultimately it goes back to the service that physicians provide to the patient, a vague but concerning presentation can get a physician concerned about whether something is missing, and even if he or she is skilled enough.  Hovering around is a concern of malpractice.  As many as 39% of medical malpractice lawsuits come from failure to make a diagnosis, missed diagnosis, or delay.   There is a point when the nonspecific, mild symptoms start to escalate to more specific, acute symptoms.  Ideally, the time to diagnose a disease is before it can cause a threat to health.

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The Diagnostic Challenge: A Framework

Fortunately, there are some important aspects to addressing a challenging diagnosis for patients and doctors alike. Therefore, I approached the patient with the diagnostic dilemma with these points in mind:

Go back to the History and Physical Exam.

This is one of the physician’s most important tools. Whenever I get into a situation of a diagnostic challenge, I go back to the patient and listen again to his/her words and determine the development of symptoms.  A dying art in the era of advanced medical technology, a good history can still assist greatly in making a diagnosis; from some estimates, 70-90% of the time.

A follow-up physical examination while reviewing the history is critical.  I often find that the best exam includes a second visit.  It clarifies the history:   the patient may have had a chance to think about the symptoms or questions more; the exam may have been changed, or a physician may have missed something on the prior exam.

Communication

It is important to keep the channels open and to feel comfortable discussing any questions or concerns.  I like to reassure the patient that I will continue to search for a diagnosis – that I am persistent on their behalf. The person can contact me and inform me of their status. We can keep visits at closer intervals to review progress.

Go toward the place where there is the greatest change.

A blood test can sometimes show changes in time, for instance, in the white blood count or the liver tests. In addition, a patient may have localizing symptoms, for instance, localized abdominal pain.  If there is a concern, an imaging test may be ordered, such as a CT scan.  Where there is an abnormality, a more invasive test to assist in the diagnosis is necessary.  This often requires a scope or interventional radiology to take a sample.

Watchful waiting requires diligence from the doctor and patient.

If a person is not suffering from severe symptoms, they may be safe enough to monitor over time.  This requires careful planning and setting goals.  It is helpful that the patient is seen more frequently or receives additional testing, such as an imaging study or diagnostic test, in a timely fashion.  I once diagnosed a patient with atrial fibrillation in the infectious diseases clinic but needed to confirm it with an ECG, which we didn’t have.  What ID clinic needs an ECG machine anyway?!

I sent him to the cardiovascular lab; it was closed.  He couldn’t get the test for one week, which confirmed the clinical exam and the reason for his fatigue – not Tularemia that he thought he had. Though, it took a week to get the ECG.

Consider collaborative discussions, involvement, and second opinions

Occasionally bias can obfuscate the ability to draw objective conclusions.  There are always going to be knowledge gaps, as well.  I used to think that being a specialist would have a more confined and manageable knowledge foundation than a generalist.  I thought wrong.   It is just as complex and ever-developing. Just look at the COVID-19 pandemic.

Commonly, a patient’s information is discussed by multiple providers involved.  In fact, it is a disservice not to have collaboration.  It isn’t unusual and sometimes helpful to walk down to the radiology reading rooms, review slides in microbiology or the biopsies with a pathologist, or to scrub in on a surgery.  These perspectives enhance care and can sometimes pick up things that weren’t noticed before.

I discuss cases with other infectious diseases specialists if I can’t find a satisfactory answer from my knowledge base or a brief literature review.  Sometimes, one can be treated while closely watching and considering other causes.  Other times, it is necessary to wait until a definitive diagnosis is made.  It all depends on the acuity.

Conclusion

More frequently than not, there come times in a physician’s practice where there is a level of discomfort in making a diagnosis – the pieces don’t add up. Instead, it forces us to think and consider alternative causes and reframe prior interpretations.

It is important to embrace these situations and remember that a patient is wrestling with this uncertainty. Therefore, a strong doctor-patient and doctor-doctor collaboration are crucial to push ahead and understand the reasons behind the changes that are being seen in the body.

A distressing feature in the life which you are about to enter, a feature which will press hardly upon the finer spirits among you and ruffle their equanimity, is the uncertainty which pertains not alone to our science and art, but to the very hopes and fears which make us (humans). In seeking absolute truth we aim at the unattainable, and must be content with finding broken portions. Sir William Osler