Introduction

Arcanobacterium haemolyticum (A. haemolyticum) is a non-spore-forming, aerobic, gram-positive bacillus that causes pharyngitis and rash in children and young adults^1,2. The highest incidence is reported between the ages of 15 and 18, reaching up to 2.5% ^2-4.

Among the reported pharyngitis series, a slight predominance in females has been observed, whereas systemic infections caused by A. haemolyticum show a tendency toward males³. No seasonal prevalence has been reported¹.

The typical form of presentation is odynophagia, fever, and rash, often indistinguishable from that caused by group A streptococci^1-5. Exceptionally, it can cause invasive systemic infections, mainly endo carditis, osteomyelitis, meningitis, and pneumonia. These occur mainly in adults with comorbidities such as diabetes and other immunocompromising condi tions, although there are descriptions in healthy hosts^1,6.

Regarding microbiological diagnosis, its slow growth may lead to it being overlooked in cultures, but its detection does not require special processing of the sample. Current bacterial identification me thods, such as mass spectrometry, have facilitated their identification^1,3,7.

For treatment, both penicillin and erythromycin are effective. The prognosis in cases of A. haemolyticum pharyngitis is good, even in untreated patients¹.

There are no reports of clinical cases of infection by this microorganism in Uruguay.

We present the case of a previously healthy adoles cent with the typical clinical manifestations of A. hae molyticum infection, intending to raise awareness of this etiology within the scientific community.

Clinical case

A 14-year-old adolescent, previously healthy, and up-to-date vaccinations, presented to the pediatric out patient clinic with a 72-hour history of odynophagia, without fever. He also reported mild headache and as thenia. Pruritic skin lesions appeared on his limbs. No other respiratory symptoms were present. On physical examination, the patient was alert, responsive, and in good general condition. Hemodynamically stable and afebrile. Skin lesions were observed on the upper limbs over both elbow joints and the lower limbs, in volving the dorsum and soles of both feet. The lesions were macular, erythematous, with well-defined bor ders, and pruritic (Figure 1). No enanthem was obser ved. The pharynx appeared congested (Figure 2). Pain ful cervical lymphadenopathy was present, but not palpable in other areas. The rest of the physical exami nation was unremarkable.

Figure 1 14-year-old adolescent, pharyngitis and rash due to A. haemolyticum. Macular rash on the foot and forearm. 

Figure 2 14-year-old adolescent, pharyngitis and rash due to A. haemolyticum. Congestive pharynx. 

A rapid antigen detection test for S. pyogenes was performed, which was negative. Empirical treatment with oral clindamycin was initiated pending the results of the pharyngeal culture.

The throat swab culture yielded A. haemolyticum after 48 hours of incubation. The isolate was suscepti ble to penicillin and erythromycin. Microorganism identification was performed using mass spectrometry (VITEK^® MS Maldi-Tof), and antimicrobial suscep tibility was determined using a gradient strip (E-test).

At the 24-hour follow-up after starting treatment, the patient showed improvement in the skin lesions, no signs of pharyngitis were observed, and remained with no fever. Treatment was changed to amoxicillin, com pleting a total of 10 days with good clinical progress.

Discussion

A. haemolyticum was first identified as Corynebacte rium haemolyticum in 1946 in pharyngeal cultures from World War II soldiers and Pacific Islanders with pharyngitis, which was clinically indistinguishable from infection caused by group A streptococci³. Since 1982, it has been reclassified into the new genus Arcanobacterium, with A. haemolyticum as a single species⁸.

Recently, it has been in creasingly associated with pharyngitis and rash(3). Although, so far, there are no reports of cases with this clinical presentation in the pediatric population.

Pharyngitis is the most common finding in A. haemolyticum infection, presenting with odynopha gia and fever¹. Pharyngeal erythema is universally present and tonsillar exudate is common and occurs in up to 70% of cases. Lymphadenopathy occurs in 26% to 81% of reported patients, mainly affecting the anterior cervical or submandibular lymph nodes bilaterally³. These symptoms, described as typical of the disease by A. haemolyticum, are those presen ted by the patient, without being able to clinically rule out other etiologies.

Generally, in up to 75% of cases, a skin rash appears 1 to 4 days after the onset of odynopha gia^3,6. This rash is toxin-mediated, similar to what happens in infections caused by group A streptoco cci¹. It is a scarlatiniform rash that begins in the distal extremities and then spreads centrally to the trunk and neck, most frequently affecting the exten sor surfaces. It affects the face, palms, and soles. In 50% of cases, it is associated with pruritus. Urticaria and erythema multiforme have also been described. The rash persists between 2 and 5 days, and even tually, a slight desquamation of the skin on the hands and feet follows^(3,6). As evidenced in the ima ges, the case we report included the rash, within the expected time frame, on extremities and affecting the extensor surfaces, further supporting this etiology.

This disease, typical of A. haemolyticum, is clinically indistinguishable from the one caused by group A streptococcus¹. Findings such as circumo ral pallor, Pastia’slines, and strawberry tongue are observed in scarlet fever but do not occur in A. haemolyticum infection^1,6. Our patient did not pre sent these differential signs of Streptococcus pyo genes (S. pyogenes), nor the typical rash distribution starting around the neck and extending to the trunk and extremities. However, due to its higher frequen cy, a differential diagnosis with this pathogen was considered, which led to performing a rapid strepto coccal antigen detection test as an initial step. With the negative result, this etiology was quickly ruled out. It is worth noting that we found no reports of cross-reactivity in these tests with A. haemolyticum.

Sayad E et al, in their systematic review on the burden of A. haemolyticum pharyngitis, suggest a diagnostic and management algorithm based on a systematic approach with emphasis on medical history, patient age, absence of a viral prodrome, and a negative rapid S. pyogenes test as clues for diagnosis, high lighting the need in these cases for confirmatory culture⁹.

Other common causes of pharyngitis and rash in adolescents and young adults are infections by Myco plasma pneumoniae, Neisseria gonorrhea, and many other pathogens including viruses such as influenza or Epstein-Barr virus¹. Viral etiology in this patient should have been considered because of the headache and asthenia as accompanying symptoms. Kawasaki disease, toxic shock syndrome, primary HIV infection, and secondary syphilis are other possible differential diagnoses¹⁰. In some cases, rash has been observed before the development of pharyngitis, which raises other diagnoses. Carlson et al. reported the clinical case of a 19-year-old patient who initially presented with skin rash, followed by pharyngitis and fever, which initially led to a diagnosis of an allergic reaction¹⁰.

To confirm the diagnosis of A. haemolyticum infec tion, isolation of the microorganism is required from a throat culture, a skin lesion, or a sterile body site in the case of invasive infections¹. However, this isolation presents certain challenges such as the fact that A. hae molyticum can be found in the pharynx and skin of healthy individuals as a commensal which signifi cantly hinders the diagnosis, and identification of the microorganism must be supported by clinical suspi cion¹¹. Moreover, A. haemolyticum isolates from pha ryngeal exudates can be mistaken for streptococci and Corynebacterium diphtheriae. It may also be isolated concomitantly with other bacteria, such as group A streptococci and other streptococcal species³. In addi tion, A. haemolyticum has slow hemolysis, between 48 and 72 hours, whereas streptococci undergo beta hemolysis rapidly on sheep blood agar, within 24 hours, which often leads to plates being discarded be fore A. haemolyticum hemolysis occurs⁶. Thus, many infections may go undetected due to the slow growth and hemolysis in culture, especially if streptococcal antigen tests or nucleic acid amplification tests are performed without a supporting pharyngeal culture. Therefore, if an infection by this microorganism is sus pected, particularly in an adolescent or young adult with pharyngitis and rash, a pharyngeal culture should be performed and it should be considered to inoculate media containing human or rabbit blood or use sheep blood agar for ≥72 hours, in order to identify the small hemolytic colonies of A. haemolyticum³.

Accordingly, the Infectious Diseases Society of America (IDSA) currently recommends confirmatory bacterial testing in any case of pharyngitis, excluding those with an evident viral infection, due to the signifi cant overlap in signs and symptoms between S. pyogenes and other infectious organisms such as A. haemolyticum^12,13. In our institution, all pharyngeal samples obtained from patients with clinical diag nosis of pharyngitis and negative rapid antigen de tection tests for streptococcal antigens, are submitted for culture.

Gastón et al. reported three clinical cases of previously healthy 20-year-old patients who pre sented with pharyngitis and rash, with or without fever. Their cultures were negative for S. pyoge nes, heterophile antibody tests for Epstein-Barr virus were negative, and A. haemolyticum was grown in the pharyngeal culture, with good reco very after antibiotic treatment with penicillin or erythromycin¹³.

In the patient, A. haemolyticum was isolated given the identification of the microorganism using mass spectrometry available at our institution. Matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry, as well as 16S ribosomal RNA (rRNA) amplification techniques, gene sequencing, and denaturing high-performance liquid chromatography (DHPLC), are more specific identification methods that allow for confirming the diagnosis³.

More rarely, A. haemolyticum can cause deep and systemic infections. Isolated cases have been des cribed, including Lemierre's syndrome, brain abscess, meningitis, meningoencephalitis, orbital cellulitis, endocarditis, osteomyelitis, septic arthritis, deep soft tissue infections, empyema, cavitary pneumonia, py othorax, sinusitis, bacteremia, and sepsis^1,6. In 2009, Fernandez-Suarez et al. reported the first case of Lemierre's syndrome caused solely by A. haemoly ticum. It involved a previously healthy 23-year-old man with acute pharyngotonsillitis and subsequently developed Lemierre's syndrome¹⁴. Most of these se rious infections occur in adults and are frequently associated with previous soft tissue infections, post traumatic wound infections, or underlying conditions such as diabetes, peripheral vasculopathy, neoplasms, immunosuppression, or intravenous drug use^1,6. However, Gu et al. described a clinical case of a soft tissue infection in an immunocompetent 7-year-old child, highlighting that the ability of this pathogen to cause more severe infections in otherwise healthy hosts should not be underestimated¹⁵. In the sys tematic review by Sayad et al., at least 11 compli cations were reported among 191 previously healthy young patients, including peritonsillar abscesses, Lemierre's syndrome, pneumonia, sepsis, and menin gitis⁹. Therefore, while invasive A. haemolyticum disease typically occurs in immunocompromised hosts, immunocompetent individuals can also deve lop severe illness.

Regarding treatment, there are practically no reco mmendations due to the small number of reported cases and scarse clinical experience¹¹. According to the literature, A. haemolyticum is susceptible not only to penicillin and erythromycin, but also to other β lactams, clindamycin, chloramphenicol, azithromycin, vancomycin, ciprofloxacin, tetracyclines, and rifampi cin. In contrast, most strains are resistant to sulfona mides and trimethoprim-sulfamethoxazole¹. Some authors have reported the existence of in vitro penicillin-tolerant strains^14-16. Therefore, erythromy cin has been suggested as first-line treatment for pha ryngitis caused by this pathogen, considering that although almost all A. haemolyticum strains are highly susceptible to erythromycin, it is not bactericidal¹. In this case, although A. haemolyticum was sensitive to clindamycin, treatment was adjusted to an aminopenicillin, with good clinical outcome and no evidence of the previously described tolerance to this class of antimicrobials.

Neither the benefit of antimicrobial therapy for A. haemolyticum pharyngitis nor the comparative effica cy of therapeutic agents has been established in pros pective randomized clinical trials. No recognized post-infectious complications have been associated with A. haemolyticum pharyngitis¹⁷.

In relation to deep infections and sepsis, the few references available suggest treating with high dose intravenous penicillin as the first choice, with or without gentamicin. Alternatively, penicillin can be used in combination with an aminoglycoside⁶. In any case, the treatment of systemic infections should be adjusted according to the antibiotic susceptibility profile and the site of infection¹⁷.

Long-term sequelae of A. haemolyticum infection have rarely been reported. Persistent infection due to delayed recognition of the organism as the causative agent may lead to increased morbidity and mortality, especially in patients with comorbidities⁶.

Conclusiones

In conclusion, the clinical case presented highlights the importance of considering A. haemolyticum as a causative agent of pharyngitis and rash, especially in adolescents and young adults. This microorganism, often overlooked due to its similarity to other pathogens, can cause symptoms that mimic streptococcal pharyngitis. In addition, A. haemolyticum has been observed to cause severe and systemic infections in rare cases. Therefore, a high index of suspicion is required for timely diagnosis.