An ongoing dialogue on HIV/AIDS, infectious diseases,
December 19th, 2022
Chaos in the Diagnosis of Pneumocystis Pneumonia
Confession — no one knows the best way to diagnose Pneumocystis jirovecii pneumonia, commonly abbreviated as PJP, or for some stubborn old timers, PCP.
Don’t believe me? Take a look at this poll — not just the results, but the extraordinary diversity of responses — then head on back here for a historical perspective sure to excite ID, pulmonary, oncology, transplant, and rheumatology geeks the world over.
Hey ID clinicians of #IDtwitter, what are you using for first-line Pneumocystis jirovecii diagnosis on respiratory samples in your center/hospital? Would be helpful to hear why. Thanks!
— Paul Sax (@PaulSaxMD) December 5, 2022
So how did we get to this confusing state of affairs?
For many years during my early ID career, diagnosis of PJP was by microscopy only — literally seeing the organisms under a microscope. You couldn’t culture this tricky fungus in standard labs, so you needed to examine sputum, or fluid from bronchoalveolar lavage (BAL), or in really tough cases, tissue from a lung biopsy. The sensitivity of microscopy, especially on induced sputum — respiratory secretions obtained by having the patient breathe nebulized hypertonic saline — varied widely depending on the quality of the sample and the skill of the person doing the microscopic exam.
Back in the early 1990s, we were lucky to have a highly skilled microbiologist named Walter working in our hospital lab. Among his many talents was his uncanny ability to spot the characteristic “apple green” cysts of Pneumocystis jirovecii on immunofluorescence stains of induced sputum samples, sparing patients more invasive procedures (bronchoscopy or lung biopsy). That’s a picture he sent me years ago for teaching purposes, in case you’re wondering. During an 18-month period roughly from 1992-4, Walter made this diagnosis over 100 times, almost all of them from induced sputum specimens obtained from people with HIV — it was before we had effective HIV therapy.
Fast-forward a decade or so, to the mid-2000s, when I had the opportunity to visit the Cleveland Clinic for an educational event. The trip included a tour of the microbiology laboratory, the capabilities of which absolutely floored me. Wow, what an impressive place! First, the lab was GIGANTIC. Second, it did all sorts of cutting-edge diagnostics that we could only dream about in our hospital lab. One of these tests they did was pneumocystis PCR on respiratory secretions or BAL fluid, with the head of the lab, Dr. Gary Procop, telling me it all but replaced immunofluorescence staining at their center.
He also told me PCR was much more sensitive in the patient population that increasingly made up the majority of cases of PJP — non-HIV immunocompromised hosts. PJP incidence in PWH had dropped dramatically with effective ART, and one was much more likely to see a case of PJP in a transplant recipient, or in someone being treated for cancer or an autoimmune condition.
The problem with PCR? Some people with positive tests arguably had colonization only, not disease, hence it required clinical judgment to interpret the results correctly. This phenomenon is sometimes referred to as a “false positive”, but more accurately it’s the “true, true, but unrelated” situation. They have pneumonia (true), they’re PCR positive (true), but something else is causing it.
Meanwhile, another test entered the picture at around the same time, blood beta-glucan. Beta-glucan is a component of the cell wall of many fungi, including Pneumocystis — hence people with PJP often have positive beta-glucan tests.
Note that I didn’t even mention it in the above poll, because it’s very different from microscopy and PCR. How different?
- It’s a blood test. It’s much easier to obtain than respiratory secretions.
- It’s quantified. Some “positive” tests are much more positive than others.
- It’s non-specific. A bunch of other fungi, including candida and histoplasmosis, also trigger a positive test — as does a boatload of non-infectious things, including surgical gauze, intravenous immune globulin, hemodialysis, certain medications, owning a pet rabbit (made that up), who knows what else.
It’s this lack of specificity that makes beta-glucan results such a head-scratcher for clinicians. On ID consult services around the country, many will recognize (and groan) at the “we sent a beta-glucan, it’s positive, and we don’t know what to do with it” consult. It rivals the “5 days post-cardiac surgery, has leukocytosis, unclear cause” consult in frequency.
But the convenience of beta-glucan makes it irresistible, and we adopted it with great enthusiasm at our hospital — so much so that the residents began referring to getting a “g and g” on many admissions, shorthand for “glucan and galactomannan.” Plus, under the right circumstances, it obviated the need for an induced sputum or a bronchoscopy. Specifically, in a classic case of HIV-related PJP, a beta-glucan > 500 had a very high predictive value positive for the diagnosis. Unless you’re practicing in histoplasmosis-endemic regions, usually no further testing is needed.
So where does that leave us? How can a practicing ID clinician make their way forward with these three diagnostic tests battling it out?
Faced with a microbiology lab overwhelmed with COVID-19 and a shortage of technicians, we’ve stopped doing microscopy for PJP (Walter has retired, alas), and instead, just offer PCR. It’s a send-out test that takes a few days to come back. (I was surprised that some of the respondents to my above poll said it took over a week! It’s not like they need to get the genetic sequence of the bug.) Blood beta-glucan is still available as well.
So here are my observations so far, with the caveat that I work in a region with a relatively small population of untreated people with HIV (we have amazing ART access in Boston) and a very large population of non-HIV immunocompromised hosts.
- PCR is more sensitive than microscopy. Gary Procop was right.
- The incidental positive PCR test isn’t such a big deal. As noted, we have a lot of immunocompromised people here. We tend to believe the positive tests mean something. Gary was right about this, too.
- Beta-glucan is still sometimes useful — but only when sent with a reasonable pre-test probability of PJP. Otherwise, you’ll be dealing with a ton of perplexing positive results.
Especially if the patient owns a pet rabbit.
Can’t get enough on this topic? Here’s a terrific review of all things pneumocystis, by a couple of local experts.