We discussed the initial 1-3 days of sore throat last time (Sore Throat – 1). Once it’s gone on 4 to 5 days or more, it’s a different differential.
TABLE — CAUSES OF PHARYNGITIS
|1-3 Days Duration||
>4-5 Days Duration
If a sore throat has persisted at least 4 days, without any typical URI symptoms, we can eliminate a “simple virus” as the cause. We can probably drop Strep as well, which invariably resolves on its own by then. Still, we do usually obtain a Rapid Test, not because Strep is likely, but it’d be embarrassing to engage in any further work-up without it.
We obviously remain alert to “Don’t Miss” conditions (see posting Sore Throat – 1).
The extent to which we order laboratory tests depends on the clinical scenario, patient risk factors, and insurance coverage [aka “cost-effectiveness”]. Let’s cover them.
** MONONUCLEOSIS — Common in teens & young adults; kids are less symptomatic, & older persons are already immune. Caused by Epstein-Barr Virus (EBV).
Suspect Mono when fatigue is prominent. Be alert for tender lymph nodes in unusual locations, especially the posterior cervical, also the suboccipital, axillary, epitrochlear. Splenomegaly virtually clinches the diagnosis, though it’s usually not palpable.
Unfortunately, the Heterophile Agglutination test for Mono, commonly known as the Monospot, is not very sensitive in early illness. It sometimes takes 3 or 4 weeks to convert. The specific “Epstein-Barr IgM Antibody” is better, though sometimes it too may be negative, requiring other (even more expensive) antibodies.
The most sensitive sensitive tests include the CBC, with a manual differential by peripheral smear to look for “atypical lymphocytes,” and liver transaminases (ALT & AST). But, of course, they’re not specific. For sure-fire diagnosis, prescribe Amoxicillin, which causes a morbilliform (maculopapular) rash up to 100% of the time [actually, maybe don’t prescribe it].
When it clinically seems like Mono, but the Monospot is negative, and the patient is not very ill, we can usually make a tentative diagnosis & repeat weekly Monospots. But I’ve seen a few clinicians fret & sweat when working up, not “sore throat,” but rather cervical adenopathy. If fine-needle aspiration is non-diagnostic, they’re torn between waiting out the Monospot and missing lymphoma, or going for an excisional biopsy. That’s the time to order EBV & all other antibody tests (depending on lab turnaround time).
And of course, some experts say that any time you think “Mono,” also think (and address) Primary HIV.
** PRIMARY HIV — a.k.a. “Acute Retroviral Syndrome,” “Acute HIV.” Incubation period from the moment of transmission is 1½ weeks to 30 days. Symptom duration is 1-3 weeks.
Initial studies found that around 50% of newly-infected persons experience a range of symptoms:
- Fever, Malaise, Generalized Lymphadenopathy — most common
- Sore Throat, Rash, Arthralgias/Myalgias, Headache — common
- Diarrhea, Oral/Genital Ulcers, Nausea/Vomiting — less common
Like Mono, the lymphadenopathy is atypical. Posterior cervical nodes are common. Suboccipital, axillary, and epitrochlear are very suspicious.
The rash, which may occur in up to a third of cases, is morbilliform (literally “measles like), i.e. maculopapular. It may be prominent or subtle. A few pictures:
Subsequent literature suggests that upon extensive inquiry, actually up to 80% of HIV-positive persons recall some sort of minor illness around the time of likely transmission, probably an acute retroviral syndrome. So clinically, many persons may be minimally symptomatic.
This is the “Window Period,” when standard HIV-Antibody testing is negative. Sero-Conversion from day of infection occurs approximately at:
- 1 month — 50% of persons
- 3 months — 95%
- 6 months — >99%
Diagnosis of Primary HIV is made by “Viral Load” testing for “HIV-1 RNA by PCR.” The test is strongly positive at this time, with titers approaching 1,000,000 copies/ml. Indeed, patients are so viremic (& consequently so infectious), and the test so sensitive, that low level titers (e.g. <1,000 copies) should be dismissed as laboratory error from airborne contamination.
But Viral Load tests are expensive ($100 – $200); we can’t order them on everyone. Presence of risk factors is helpful, but some patients may not be forthcoming. It’s hard to argue with a self-pay patient who swears they have no risks. In such cases, I emphasize the potential for transmission during Primary HIV, and settle for serial antibody testing.
** GONORRHEA — There’s very little information on the natural history of pharyngeal gonorrhea, because asymptomatic colonization is so common. That means, if a patient with sore throat cultures positive for the gonococcus (GC), there’s a decent chance that something else (like a simple URI virus) may be the true causative pathogen. Still, treatment is indicated 1) to prevent further transmission; 2) to prevent the very unlikely possibility of dissemination; and 3) for mere aesthetics if nothing else (who wants to walk around knowing there’s GC in their throat?).
Physical exam won’t help a bit in identifying pharyngeal gonorrhea. Suspect it in persons who’ve had oral sex. Oral sex on a man is probably much more conducive to transmission then on a woman, but there’s no good data.
(** Chlamydia) — There’s no good evidence that Chlamydia trachomatis affects the pharynx, and some evidence that it doesn’t.
** Mycoplasma — This entity warrants lower case bold because there’s some suggestion in the literature that Mycoplasma pneumoniae might cause pharyngitis en route to causing pneumonia. But clinically it’d be virtually impossible to identify in time. Would be inane to advocate for empiric azithromycin, unless you argue that there’s already so much pneumococcal resistance around, we’ve nothing to lose.
** HERPES SIMPLEX VIRUS — One study found almost 10% prevalence of HSV-1 among college students with sore throat; of course, much of that might represent asymptomatic viral shedding during unrelated pharyngitis. Some case reports identify severe primary HSV-2 pharyngitis after recent oral sex. I’ve swabbed a few throats for Herpes over the years, when patients complained of recurrent pharyngitis, but never found it. Now I’ll only seek it if I see actual vesicles in someone with a history of frequent bouts.
** UNCOMMON BACTERIA — Various bacteria seem capable of causing acute pharyngitis, presenting just like Strep, viruses, or any other etiology. They include Non-Group-A Streptococci (mainly groups C and G) and Arcanobacterium haemolyticum. They can be diagnosed by complete throat culture [which we never order] and resolve on their own without sequelae anyway.
** SYPHILIS — Secondary syphilis can definitely cause pharyngitis. However, there are invariably other findings, such as fever, generalized adenopathy, rash (check palms & soles), condylomata lata (moist gray plaques on mucus membranes), etc. Indeed, pharyngitis as a sole manifestation of secondary syphilis is so unlikely that I no longer check RPRs for it.
If you do order an RPR or VDRL, expect a high titer (e.g. ≥1:16, usually lots more). A low titer (e.g. ≤1:4) suggests sero-fast Late-Latent Syphilis, of truly unknown duration. The latter requires 3 weekly injections of Benzathine Penicillin 2.4 million Units IM (& some thought re: any suggestions of 3° disease), whereas for 2° Syphilis it’s only a one-time shot.
Many of the above clinical findings of 2° Syphilis also occur with Primary HIV Infection. Incubation periods differ, however. Manifestations of 2° Syphilis begin 4-12 weeks after infection (and may recur intermittently for a year). Primary HIV occurs within a month of infection.
** TULAREMIA — Another 3rd World disease when involving the throat, caused by contaminated food or water. In the US, most tularemia presents as focal adenopathy, plus or minus ulcers with central eschar at the portal of entry, though tick-borne tularemia could affect the throat if you pull out a tick & lick your fingers.
Suspect as a cause of moderate-severe Pharyngitis if you see fever, oral ulcers, prominent nodes, and otherwise negative work-up (and no response to penicillin if prescribed). Diagnosis by antibody titers is hard, but the only way. If the test is positive, consult Infectious Disease for interpretation. Clusters of Tularemia get reported as possible bio-terrorism.
** NEUTROPENIA — I always obtain a CBC when patients complain of unremitting sore throat lasting more than 4-5 days — mostly to check for Mono, but it’ll certainly catch neutropenia due to leukemia or whatever. As we mentioned last posting, worry here if you see bullae, or even maybe vesicles, or if a patient is taking a causative medication. Worry more if there’s fever.
** RABIES (early) — Just to be complete; a fair number of patients with human rabies present initially with “sore throat” (& invariably leave with penicillin). In its early stage, before onset of frank CNS symptoms, the only clue might be agitation at sight of water (hydrophobia), or with a whiff of air across the face (aerophobia). Index of suspicion is raised if there’s a history of animal bite during recent 3rd World travel, and subsequent paresthesias at bite site, though most US rabies is from bats (bat bites aren’t noticed). Incidence is 50 cases since 1990 in the U.S.; do leave a comment if you find one!
Post-Script: Since bat bites aren’t noticed, the CDC recommends rabies prophylaxis if you awaken from sleep & see a bat in room (or if bat is found in a room with a child or mentally-incompetent adult [including drunks]).
SO, WHAT DO WE DO…
When a patient presents, or returns, with persistent pharyngitis lasting more than 4-5 days?
- Strep throat screen, of one form or another, if not yet done.
- CBC with manual differential (for atypical lymphocytes; also shows absolute neutrophils)
- Liver Function Tests (looking for slight elevation of transaminases ALT / AST)
- Maybe a GC probe or culture, if there’s a history of very recent oral sex on a new partner (esp. a male)
- ??? Maybe a test for Herpes simplex [but only if there’s a history of recurrent sore throats, & I see vesicles to swab]
- Review risks for Primary HIV
The CBC & LFTs are pretty sensitive for Mono, the Monospot is specific. the CBC will also reveal a rare case of neutropenia.
If the CBC / LFTs are suggestive, make a tentative diagnosis of Mono. But get a good history of risk-factors for HIV infection within the past 9-30 days. If the latter is worrisome, strongly consider ordering both an HIV-Antibody (the standard screen) and an HIV-1 Viral Load (HIV-1 RNA by PCR). Primary HIV resembles Mono in virtually all aspects.
Assuming Primary HIV is only a theoretical possibility (e.g. history of monogamous unprotected sex), reassure that though the condition exists it’s highly unlikely, but do casually hint that the virus would be extremely transmissible (to convey the message in the event your history-taking was somehow lacking). If patient’s partner was in fact the index case, well, they’ve already got it. If patient remains concerned, they can get serial antibody screens at 1, 3, and 6 months.
When the Monospot is negative, but patient remains symptomatic, especially in terms of malaise & fatigue, keep repeating the test weekly. Depending on level of illness, you can order the more sensitive Epstein-Barr Virus Antibody, both IgM & IgG. The IgM makes the diagnosis, the IgG rules it out (long-term immunity from remote infection). If they’re even sicker, look up additional antibodies to Mono.
Of course, cytomegalovirus & other viruses can produce a mononucleosis-like syndrome, so the Monospot may always remain negative. If the Monospot is positive, that’s all there is to it… almost. There are reports of false-positive tests during Primary HIV.
With all these viral infections, pharyngitis loses prominence to fatigue and malaise. But what if the latter are lacking, and all the patient complains of is a nagging sore throat, that goes on and on (even months). Though there’s no good data, I empirically offer one of the following treatments as a “therapeutic” (i.e. Diagnostic) Trial:
- Presumed “Allergic Nasopharyngitis” — a non-sedating antihistamine plus a nasal steroid.
- Presumed GERD — a high-dose proton pump inhibitor, e.g. omeprazole 40 mg qd or even BID.
I treat for 1-2 weeks. If successful, I continue therapy (but decrease the PPI to a standard dose). If symptoms remain unchanged, I go for the other empiric treatment. If that’s no help either, I explore mood symptoms, and treat as such if somatic disorder or depression appear plausible. Eventually, may bail out to ENT, but that’s only happened to me [for pure “sore throat”] once in the last 20 years.