Rare Infectious Diseases: A Tutorial

Rare Diseases

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The Genetic and Rare Diseases Information Center of the National Institutes of Health (NIH) defines a rare disease as one that affects fewer than 200,000 people.¹ According to the NIH, there are more than 7000 rare diseases in the United States, affecting more than 30 million—approximately 1 in every 10—people in the country.²

Given that February is Rare Disease Month, it seems appropriate to discuss how a physician or scientist may go about diagnosing a disease that is not common. When I suspect a patient may have an infection, I first consider whether it is likely to be bacterial, viral, fungal, or parasitic. Sometimes a condition may fit in more than 1 etiology, but you can usually narrow it down at the outset and focus on more likely etiologies for the initial workup.

Often, it’s helpful to look at individual risk factors:

1. Where is the person from?

2. Have they traveled to an area where specific infections are endemic?

3. Do they have occupational risks for infection?

4. Do they have immune deficiencies that put them at risk for uncommon infections?

The clinician must consider these factors, and if nothing jumps out immediately, start a fairly broad workup of the more likely infectious agents. A common first step is to collect cultures of blood and fluid from parts of the body thought to be involved in the infection (urine, sputum, or cerebrospinal fluid, for example) to see whether causative organisms are present For example, I had a brucellosis patient who had been experiencing fever and fatigue for several weeks. He had just traveled to the US from Mexico, where he had been consuming raw milk and fresh cheese almost daily. Brucellosis is not an infection we often see in Minnesota (only 26 were reported in the state between 2007 and 2019),³ but this patient had the right risk factors for it.

If the initial workup doesn’t explain the condition and you still think the patient has an infection, there are specialized tests to consider, like the 16s and 28s rRNA polymerase chain reaction (PCR) assays. For these, a sample of a normally sterile bodily fluid in which infection is suspected (blood, cerebrospinal fluid, joint aspirate) is sent to a specialized lab, which amplifies any RNA present in the sample and compares it to a database of bacterial (in the case of 16s) or fungal (28s) genetic sequences to see whether any organisms of interest are present. If the organism is difficult to grow or detect with standard laboratory measures, these assays can often provide more insight and help diagnose uncommon infections. PCR-based testing and other molecular techniques have become a mainstay of diagnostics for infections in the US, and they are typically fast and specific.

When the Answer Can’t Be Found

Sometimes, however, even a broad and aggressive workup won’t yield an answer. For example, my colleagues at M Health Fairview University of Minnesota Medical Center and I saw an elderly man with a dramatic neurologic presentation that included muscle weakness and waxing and waning confusion. He was positive for insect- and tick-borne infection risk factors: he lived in a rural area, went hiking/camping frequently, and had recently been bitten by insects and exposed to ticks. We performed a broad infectious workup, looking for common tick- and insect-borne infections, as well as more routine bacterial and viral etiologies of meningoencephalitis, but nothing came back positive. The patient seemed to get a little better with a treatment targeting Minnesota’s common tick-borne diseases but reversed course soon after.

We sent blood samples and cerebrospinal fluid samples to the Centers for Disease Control and Prevention (CDC) and the Minnesota Department of Health. We sent blood samples and cerebrospinal fluid samples for this testing, but no convincing etiology could be found. I suspect that the man’s condition could have been a rare arthropod-borne virus, like a mosquito-borne virus, that either we don’t have a name for or couldn’t identify. This sort of etiology is higher on my differential because of how similarly it presented to other conditions caused by such viruses and how he failed to respond to aggressive antibiotic therapy, which would not treat a viral infection. Unfortunately, often there are no effective, targeted therapies for viruses. The patient ultimately transitioned to an assisted care setting and, over time, had some improvement of symptoms but has not made a full recovery to date.

What Precautions Medical Professionals Should Take

Ironically, we benefit from living in the post–COVID-19 era because, although the virus is still with us, we are more aware of infectious diseases than we used to be. Today, it’s common to see hospital staff wearing masks, gowns, and gloves to prevent infection. Before the pandemic, it was atypical for clinicians to walk into a patient’s room with a mask on unless the person had a history of or significant risk for an infection subject to droplet or airborne transmission. Back then, if a patient were to have a rare or unknown infection that could spread by those routes, there was a greater risk that the medical personnel in charge of their care would also become infected.

As a side effect of the global spread of COVID-19, today we have a good amount of protection in place against rare diseases that may potentially be droplet borne or airborne. When mpox (formerly “monkeypox”) first popped up in the US, I was quite often on call for curbside consultations from hospitals in our area that don’t have dedicated infectious disease staff. I received a few calls from frontline doctors asking what special precautions they needed to take. Before the recent outbreak I had not dealt with mpox, but I told them that if they were taking appropriate COVID-19 precautions (like wearing a mask in the patient’s room and putting on gloves before touching a suspected lesion), they were probably already within the guidelines for protecting themselves against mpox. Our universal precautions do a pretty good job of protecting us from most diseases.

In many instances, as the saying goes, people tend to be afraid of what they don’t know or don’t understand. When they hear “rare disease,” they take it to mean “deadlier” or “more transmissible.” But that’s not necessarily the case; the fact that they’re rare means that they are not easily transmissible. If they were, they would not be rare.

However, that’s not a hard-and-fast rule. Sometimes it’s simply that the disease hasn’t yet found the perfect ecological niche. We saw this during the recent mpox outbreak; a few high-level transmissions (along with some possible genetic changes that are still being studied) allowed the virus to spread more widely and rapidly than in the past. But for the most part, rare diseases either have a difficult time spreading or have a narrow ecological niche. A good example is endemic fungi like Histoplasma and Blastomyces, which are becoming an increasing problem because their geographic reaches are spreading as a result of climate change.

When trying to determine how best to prevent infection in your unit, hospital, or clinic, consider the precautions the facility must take to protect not only patients, but staff as well. The CDC and the Society of Healthcare Epidemiology of America⁴ both offer guidelines. If you’re unsure what needs to be done for a given organism or infection, a safe strategy is to use the highest level of protection available until you know it’s safe to reduce it.

If I have a patient with a rare infection and I’m not sure what precaution sare necessary, either due to lack of data or clinical uncertainty, I wear a gown, gloves, and a mask until I know it’s safe to de-escalate. Overusing personal protective equipment can put a strain on supplies, but infecting staff and patients would strain them much further. Fortunately, apart from novel diseases, we typically have good, evidence-based guidelines for the level of protection necessary in health care settings.

Matt Pullen, MD

Some rare diseases may require very specific treatment or isolation conditions, like a negative pressure room. If you have diagnosed or strongly suspect such an infection, you must be sure that you’re equipped to handle it or that you can move the patient to a facility that can. A good example is Ebola. Our regional special pathogen unit at the University of Minnesota is specially equipped to handle Ebola should a case be detected in this part of the country. It takes specialized training, equipment, and protocols to handle the infection risk of a patient with severe Ebola. If you were to identify that kind of rare disease in your hospital, you would want to be sure that you can send the patient to such a facility.

Research Funding is Critical

We can always use more funding for rare disease research. As the human population density continues to rise, particularly in previously unsettled areas, and climate change alters the global environment, new or uncommon diseases have become more frequent. In recent years, we have seen this with the Nipah virus, Ebola, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and mpox. Despite this, many of these diseases remain “neglected,” receiving little in the way of funding and research. There needs to be a push for more funding so that we can tackle these diseases now, while their impact is lower, rather than waiting for the next outbreak or pandemic.

References

1. About GARD. Genetic and Rare Diseases Information Center. Accessed December 7, 2022. https://rarediseases.info.nih.gov/about

2. Rare Diseases at FDA. FDA. Published September 21, 2022. Accessed December 7, 2022. https://www.fda.gov/patients/rare-diseases-fda

3. Brucellosis, 2019. - Minnesota Department of Health. Accessed December 7, 2022. https://www.health.state.mn.us/diseases/reportable/dcn/sum19/brucellosis.html

4. The Society for Healthcare Epidemiology of America. SHEA. Accessed December 7, 2022.https://shea-online.org/