Parinaud’s Oculoglandular Syndrome: A Case in an Adult with Flea-Borne Typhus and a Review

Parinaud’s oculoglandular syndrome (POGS) is defined as unilateral granulomatous conjunctivitis and facial lymphadenopathy. The aims of the current study are to describe a case of POGS with uveitis due to flea-borne typhus (FBT) and to present a diagnostic and therapeutic approach to POGS. The patient, a 38-year old man, presented with persistent unilateral eye pain, fever, rash, preauricular and submandibular lymphadenopathy, and laboratory findings of FBT: hyponatremia, elevated transaminase and lactate dehydrogenase levels, thrombocytopenia, and hypoalbuminemia. His condition rapidly improved after starting doxycycline. Soon after hospitalization, he was diagnosed with uveitis, which responded to topical prednisolone. To derive a diagnostic and empiric therapeutic approach to POGS, we reviewed the cases of POGS from its various causes since 1976 to discern epidemiologic clues and determine successful diagnostic techniques and therapies; we found multiple cases due to cat scratch disease (CSD; due to Bartonella henselae) (twelve), tularemia (ten), sporotrichosis (three), Rickettsia conorii (three), R. typhi/felis (two), and herpes simplex virus (two) and single cases due to tuberculosis, paracoccidioidomycosis, Yersinia enterocolitica, Pasteurella multocida, Chlamydia trachomatis, Epstein–Barr virus, and Nocardia brasiliensis. Preauricular lymphadenopathy is a common clinical clue for POGS and is unusual in viral and bacterial conjunctivitis. For POGS, the major etiological consideration is B. henselae, which is usually diagnosed by the indirect immunofluorescence serologic technique. Although CSD POGS is usually self-limited, oral azithromycin may hasten resolution. However, other possible etiologies of POGS may also arise from cat or cat flea contact: sporotrichosis, tularemia, Pasteurella multocida, or FBT. If there is no cat contact, other epidemiologic and clinical findings should be sought, because several of these conditions, such as tularemia, paracoccidioidomycosis, and tuberculosis, may have grave systemic complications. Although there are usually no long-term ocular sequelae if POGS is properly diagnosed, it still may cause prolonged ocular discomfort and require multiple physician contacts.


Introduction
Parinaud's oculoglandular syndrome (POGS) refers to unilateral granulomatous follicular palpebral or bulbar conjunctivitis associated with ipsilateral preauricular and submandibular lymphadenopathy. The lymphadenopathy may extend to the cervical or parotid lymph nodes The patient was initially placed on cefepime, metronidazole, and vancomycin by the hospitalist team for sepsis syndrome. Monospot, Epstein-Barr Virus IgM, Cytomegalovirus (CMV) IgM and IgG, human immunodeficiency virus antibody screen and polymerase chain reaction, hepatitis B surface antigen and core IgM, hepatitis A IgM, hepatitis C antibody tests and blood and sputum cultures returned negative. Serologic tests for arboviral encephalitis (California; Eastern and Western Equine), Bartonella henselae, Francisella tularensis, Brucella abortus, and syphilis were negative. Empiric doxycycline was started on hospital day 4, 100 mg by mouth twice daily. After receiving two doses of doxycycline, the patient defervesced, had significant improvement on ophthalmologic exam, and clearance of the rash; he was discharged to finish 14 days of doxycycline. A rickettsial serologic panel was obtained on hospital day 4, and resulted after the patient was discharged; Q fever phase I and II antibodies were negative, R. rickettsii IgM and IgG by the indirect fluorescent antibody (IFA) test were both 1:64, and R. typhi IgM was >1:256 and the IgG was 1:128 by the IFA test. The ophthalmology service evaluated the patient six days after admission and he was diagnosed with mild anterior uveitis based on grade 1 cellularity in the anterior chamber, trace conjunctival injection, and a decrease in visual acuity in the left eye (20/50 vs. 20/20 in the right eye); he was started on prednisolone drops four times daily. Five days later, the cellularity improved in the anterior chamber of the left eye to rare cells, and the prednisolone was tapered off. At a follow-up appointment 23 days after hospital admission, the patient had completed a 14-day course of doxycycline and reported resolution of all prior symptoms except fatigue, which had significantly improved.

POGS Due to Bartonella henselae, the Agent of Cat Scratch Disease
In CSD, the patient typically develops a flu-like illness with local or regional lymphadenopathy. Ocular manifestations occur in 5-10% of CSD cases and POGS is the most common of these [7,10]. Based on four case series of CSD, involving a total of 1589 patients, POGS occurs in 4.3% of cases of CSD [3,[10][11][12]. In 1950, Pesme first suggested that POGS was a manifestation of CSD when he observed a child with cat contact that developed conjunctivitis and preauricular lymphadenopathy [13].
A cat scratch near the eye or direct conjunctival inoculation with infected flea feces are the most likely inciting events of CSD POGS [7]. (Bartonella henselae remains viable in cat flea feces for at least three days [14]). Constitutional symptoms in CSD POGS are usually mild. CSD POGS typically presents as unilateral eye redness, foreign body sensation, and excessive lacrimation [7]. The non-tender conjunctival granuloma of CSD POGS may be initially missed, with the tender preauricular, cervical, or submandibular lymphadenopathy differentiating the condition from a bacterial or viral conjunctivitis [10]. In one series of 24 patients with CSD POGS, preauricular lymphadenopathy was seen in ten patients, submandibular in three, cervical in three, posterior auricular in one, and multiple areas of lymph node involvement in six [13]. Preauricular lymphadenopathy is a common clinical clue for CSD POGS and is unusual in viral and bacterial conjunctivitis ( Figure 1). Suppuration of the involved lymph node rarely occurs (two cases out of 48 in one series); typically, the swelling of the involved lymph nodes resolves uneventfully [10].

POGS Due to Bartonella henselae, the Agent of Cat Scratch Disease
In CSD, the patient typically develops a flu-like illness with local or regional lymphadenopathy. Ocular manifestations occur in 5-10% of CSD cases and POGS is the most common of these [7,10]. Based on four case series of CSD, involving a total of 1589 patients, POGS occurs in 4.3% of cases of CSD [3,[10][11][12]. In 1950, Pesme first suggested that POGS was a manifestation of CSD when he observed a child with cat contact that developed conjunctivitis and preauricular lymphadenopathy [13].
A cat scratch near the eye or direct conjunctival inoculation with infected flea feces are the most likely inciting events of CSD POGS [7]. (Bartonella henselae remains viable in cat flea feces for at least three days [14]). Constitutional symptoms in CSD POGS are usually mild. CSD POGS typically presents as unilateral eye redness, foreign body sensation, and excessive lacrimation [7]. The nontender conjunctival granuloma of CSD POGS may be initially missed, with the tender preauricular, cervical, or submandibular lymphadenopathy differentiating the condition from a bacterial or viral conjunctivitis [10]. In one series of 24 patients with CSD POGS, preauricular lymphadenopathy was seen in ten patients, submandibular in three, cervical in three, posterior auricular in one, and multiple areas of lymph node involvement in six [13]. Preauricular lymphadenopathy is a common clinical clue for CSD POGS and is unusual in viral and bacterial conjunctivitis ( Figure 1). Suppuration of the involved lymph node rarely occurs (two cases out of 48 in one series); typically, the swelling of the involved lymph nodes resolves uneventfully [10]. The ocular discharge tends to be serous; purulent discharge is not observed unless secondary infection has occurred [16]. The conjunctival granulomata usually measure 0.3 to 2 cm in diameter and typically involve the eyelids, but occasionally may be bulbar, forniceal, or medial canthal ( Figure  2). Lid swelling may occur, but is usually not painful. Corneal involvement is rare, and is typically limited to superficial punctate keratitis [1]. CSD POGS with concurrent neuroretinitis has also been reported [17,18]. The ocular discharge tends to be serous; purulent discharge is not observed unless secondary infection has occurred [16]. The conjunctival granulomata usually measure 0.3 to 2 cm in diameter and typically involve the eyelids, but occasionally may be bulbar, forniceal, or medial canthal ( Figure 2). Lid swelling may occur, but is usually not painful. Corneal involvement is rare, and is typically limited to superficial punctate keratitis [1]. CSD POGS with concurrent neuroretinitis has also been reported [17,18]. Bartonella henselae infection is usually diagnosed by the indirect immunofluorescence serologic technique [19] (vide infra). Although CSD POGS is usually self-limited, with the granulomata regressing over a few weeks, antibiotic administration may hasten resolution. Oral azithromycin for 5 days is the regimen of choice (500 mg on day 1, and 250 mg on days 2-5). With concurrent retinal involvement, treatment with doxycycline and rifampin is recommended [20].
The twelve cases of CSD POGS have been described in medical literature since Carither's landmark 1978 pediatric study [16] are summarized in Table 2. The age of the patients ranged from 5 to 67 years old; 58% were female. Feline exposure was noted in eleven cases. Not all of the cases provided the necessary information to determine an incubation period, but based on cases 2, 3, 7, and 12, it appears to be 1-4 weeks. It was common for patients to suffer with ocular complaints and lymphadenopathy for weeks before presenting for medical care. In 8 of the 12 cases, the diagnosis was made by serologic methods; in two cases, it was based on characteristic histopathologic findings and a history of a cat scratch. In case #3, from 1991, diagnosis was based on the now obsolete Hanger-Rose skin test [21]. In one case, the diagnosis was made by the polymerase chain reaction (PCR) from a conjunctival swab. In two cases (#1 and #2), no antibiotics were given and resolution occurred in two to three weeks; however, in another case, resolution required two months despite presumably effective antibiotics (#6). Case #4, an HIV patient with an unspecified CD4 count, had relapsing infection and required prolonged treatment with two agents. Retinitis (#5), vitritis (#12), and upper lid ptosis (#10) were observed in single cases, but no long-term sequelae were reported in any of the twelve cases. Cat scratch of eyelid, followed in 2 w by unilat eyelid swelling, ipsilat parotid swelling/pa and cervical LAD. Lymph node biopsy showed epithelioid granulomata with foreign body and Langerhans giant cells, with central necrosis. Three weeks after presentation, signs resolved.

49, M
Cat bite on upper lip 4 w prior to presenting with 3-d history of swollen L eyelids, a red eye w/mucopurulent discharge, and tender L pa LAD. Bulbar and tarsal conjunctivae injected w/follicles on the lower palpebral conjunctiva and diffuse papillary reaction. A 3mm nodule present on bulbar conjunctiva. Tetracycline and topical sulfacetamide prescribed. Conjunctival biopsy interpreted as lymphoma. Warthin-Starry stain negative Bartonella henselae infection is usually diagnosed by the indirect immunofluorescence serologic technique [19] (vide infra). Although CSD POGS is usually self-limited, with the granulomata regressing over a few weeks, antibiotic administration may hasten resolution. Oral azithromycin for 5 days is the regimen of choice (500 mg on day 1, and 250 mg on days 2-5). With concurrent retinal involvement, treatment with doxycycline and rifampin is recommended [20].
The twelve cases of CSD POGS have been described in medical literature since Carither's landmark 1978 pediatric study [16] are summarized in Table 2. The age of the patients ranged from 5 to 67 years old; 58% were female. Feline exposure was noted in eleven cases. Not all of the cases provided the necessary information to determine an incubation period, but based on cases 2, 3, 7, and 12, it appears to be 1-4 weeks. It was common for patients to suffer with ocular complaints and lymphadenopathy for weeks before presenting for medical care. In 8 of the 12 cases, the diagnosis was made by serologic methods; in two cases, it was based on characteristic histopathologic findings and a history of a cat scratch. In case #3, from 1991, diagnosis was based on the now obsolete Hanger-Rose skin test [21]. In one case, the diagnosis was made by the polymerase chain reaction (PCR) from a conjunctival swab. In two cases (#1 and #2), no antibiotics were given and resolution occurred in two to three weeks; however, in another case, resolution required two months despite presumably effective antibiotics (#6). Case #4, an HIV patient with an unspecified CD4 count, had relapsing infection and required prolonged treatment with two agents. Retinitis (#5), vitritis (#12), and upper lid ptosis (#10) were observed in single cases, but no long-term sequelae were reported in any of the twelve cases.

POGS Due to Francisella tularensis
Tularemia is a zoonosis caused by the bacterium Francisella tularensis; it has six clinical syndromes: glandular, ulceroglandular, oculoglandular, oropharyngeal, typhoidal, and pulmonary. Ulceroglandular tularemia is most frequently seen, whereas in most series, the oculoglandular form (OGT; i.e., tularemic POGS) is the least common. The severity of tularemia varies from self-limited to disseminated disease to life-threatening sepsis [29,30]. Tularemia is transmitted by ticks, mosquitoes, biting flies, and contact with various mammals. Rarely, the infection is transmitted by animal bites or by infected water, food, or dusts [29,31].
Francisella tularensis appears as small, Gram-negative coccobacilli on direct stains of exudates; it can be cultured on cysteine-enriched media but growth may be slow (up to ten days or more). Blood cultures are rarely positive. Nevertheless, culture of the organism is a potential hazard to laboratory personnel and therefore other diagnostic methods are preferred. Rapid detection is afforded by direct fluorescent-labelled antibody testing, PCR, and immunochemical antigen detection applied to exudates or biopsy specimens. The microagglutination serologic assay is typically positive ten days after the onset of illness [30].
Streptomycin is the drug of choice for the treatment of tularemia, with gentamicin as an alternative. The aminoglycosides should be administered for 10 days [30]. However, ciprofloxacin for 10 days was found to be more effective than streptomycin in one series [34]. Second-line regimens include tetracyclines or chloramphenicol for 14 days, but treatment failures and relapses occur at a higher rate with these agents as compared to the aminoglycosides. Beta-lactams and macrolides are not recommended. With antibiotic treatment, the overall case fatality rate of tularemia in the United States is less than 2% [30]. Indicators of poor response to treatment are: persistent fever; suppuration and drainage of the affected lymph nodes; an enlargement of the affected lymph nodes; and the appearance of new sites of lymphadenopathy [35]. In one series of 142 cases, 22.5% did not respond to the initial treatment, but there were no deaths [34].
Ten cases of OGT are detailed in Table 3. The cases ranged in age from 13 to 88 years old; 56% were female. Tularemia can be challenging to diagnose because of the plethora of possible exposure routes. Methods of diagnosis were: serologic methods (5/10 cases), PCR (#21), culture (#15), smear of eye exudate (#18), and smear of eye exudate, PCR, and culture in one case (#22). Antibiotic therapy failed in two of the ten cases and lymph node excision was required for resolution (cases #17 and #19). There were no fatalities.

POGS Due to Rickettsial Infections
Although there are many rickettsial species that are pathogenic to humans, POGS has only been observed in R. typhi/felis and R. conorii infections ( Table 4). The former infections are flea-borne, whereas the latter is tick-borne. Two cases of R. conorii POGS resulted from careless handling of ticks. The diagnoses were made by serologic methods in all five cases. All of the patients received doxycycline, the drug of choice for rickettsioses, and all cases resolved without sequelae.

POGS Due to Sporotrichosis
Arinella and coworkers described 26 cases of bulbar conjunctival sporotrichosis from Brazil; POGS occurred in 65% of these cases. Twenty-four patients (96%) reported contact with cats with sporotrichosis [47]. Granulomatous conjunctivitis due to Sporothrix presents with conjunctival edema, hyperemia, mucopurulent ocular discharge, grouped yellowish conjunctival nodules with a smooth, shiny surface, with or without unilateral lymphadenopathy [48]. In sporotrichosis POGS, preauricular lymphadenopathy was most frequently observed (88%), either alone or with cervical or submandibular involvement. Diagnosis of ocular sporotrichosis is based on direct microscopy and culture. Wet mounts of ocular discharge specimens treated with sodium hydroxide are examined for the presence of cigar-shaped budding yeasts. However, due to the low fungal burden of this infection, the sensitivity of direct visualization is low. For culture, the specimen is plated onto Sabouraud agar with chloramphenicol or Mycobiotic agar, followed by incubation at 25 • C, and observed for 4 weeks for fungal growth. The treatment of choice for sporotrichosis is oral itraconazole at an initial dosage of 100 mg/day for a minimum of 90 days, with discontinuation one month after resolution of ocular disease. The dose was escalated up to 400 mg per day if there was inadequate response to lower doses. All of the clinically evaluable patients in the series of Arinelli and coworkers were cured, but unspecified ocular sequelae occurred in 35% of patients. In hyperendemic areas for sporotrichosis, due to the difficulty of making a definitive diagnosis in a timely manner, empiric treatment has been advocated while awaiting culture results [47]. One month history of conjunctivitis L eye, treated with topical tobra, oflox, fusidic acid w/o improvement. On exam, swollen eyelids, conjunctival hyperemia, chemosis, mucopurulent discharge, and ipsilateral pa LAD. Prior to symptoms, eye exposed to contaminated water. Did not recall tick bite. Culture and serology for CSD, syphilis, Lyme Disease, and Chlamydia negative. Serologic testing positive for R. conorii infection. Resolved after 2-w doxy.
Three cases of Sporothrix POGS were abstracted from the literature ( Table 5, cases 28-30). Two of the three patients had cat contact. All patients were diagnosed by culture and were successfully treated with itraconazole, but one case required 60 days of treatment (#30) and another required high-dose itraconazole (#29). No sequelae were noted.

Miscellaneous Causes of POGS
In addition to CSD, tularemia, rickettsial infection, and sporotrichosis, POGS has also been seen in other bacterial infections (Pasteurella multocida, Yersinia enterocolitica, Chlamydia trachomatis, Nocardia brasiliensis, Mycobacterium tuberculosis), viral infections (Epstein-Barr Virus (EBV), Herpes Simplex Virus (HSV)-1), and paracoccidioidomycosis ( Table 6). The course of these infections varies widely. In case #31, due to P. multocida, the infection persisted for 4 months before an appropriate diagnosis was made and the proper treatment was implemented [52]. The cases due to Y. enterocolitica and C. trachomatis (#32 and #33, respectively) were complicated by corneal perforation [53,54]. By contrast, in the cases of POGS due to Nocardia and Paracoccidioides (cases #34 and #39, respectively) [55,56], the infections were quickly diagnosed and treated and resolved uneventfully.

Lymphatic and Ocular Involvement in Flea-Borne Typhus
Both lymphadenopathy and conjunctivitis are relatively uncommon in FBT, occurring in only 13% and 18% of cases, respectively [6]. Other ocular manifestations of FBT are rarely appreciated. Isolated cases of retinitis [61,62], optic neuritis [63,64], hemorrhagic conjunctivitis [65], and uveitis [66] have been reported in FBT. However, in a prospective study of nine consecutive FBT patients who received a comprehensive ophthalmologic evaluation, three patients had ocular signs and symptoms. One patient had ocular redness and slightly blurred vision, one had floaters and slight blurring, and one had a sudden decrease in visual acuity two weeks after fever onset. Furthermore, another five patients had findings on thorough eye exam. Mild vitritis was seen in five of nine patients. Six of the nine patients had an abnormal fundus exam; two patients that had a normal fundoscopic exam had abnormal angiographic results. The posterior chamber findings included white retinal lesions, retinal hemorrhages, retinal vascular leakage, hypofluorescent choroidal dots, optic disc swelling, optic disc staining, and optic neuritis [67]. Howard and Fergie observed two cases of POGS out of 213 pediatric cases of FBT over an 18-year period [68], but POGS has not been previously reported in an adult patient with FBT.

Diagnostic Approach to POGS
Even in the absence of obvious bulbar conjunctivitis, if a patient presents with an unexplained unilateral pre-auricular mass, the upper lid should be everted and examined for follicular conjunctivitis [69]. In a patient with conjunctivitis and ipsilateral preauricular lymphadenopathy, the major etiological consideration is B. henselae. Thus, an inquiry about contact with cats should be made. However, other possible etiologies of POGS may also arise from cat or cat flea contact: sporotrichosis [47], tularemia [70], Pasteurella multocida [52], or flea-borne typhus [4]. If there is no cat contact, other epidemiologic clues should be sought. Contact with rabbits or ticks would raise concern for tularemia. Tick contact has also been implicated in POGS due to R. conorii [44][45][46]. Soil exposure may be a clue to sporotrichosis, nocardiosis, coccidioidomycosis, or paracoccidioidomycosis. Flea-borne typhus should be considered in persons with POGS with possible flea contact or exposure to cats, dogs, rodents, or opossums in an endemic area. In patients with sexual contact, syphilis, herpes simplex, chancroid, and lymphogranuloma venereum have all been implicated. Bilateral conjunctivitis with bilateral preauricular lymphadenopathy is often due to adenovirus [44]. If there is no contact with cats and other epidemiologic circumstances suggest another potential diagnosis, it is important to perform an appropriate diagnostic evaluation because several of these conditions, such as tularemia, coccidioidomycosis, paracoccidioidomycosis, and tuberculosis may have grave systemic complications.
If cat contact is confirmed in a case of POGS, empiric therapy with oral azithromycin for 5 days should be considered. The diagnosis of B. henselae infection is usually confirmed by serologic testing by the indirect immunofluorescence assay (IFA), which has a sensitivity and specificity of 90% in immunocompetent persons. In acute B. henselae infection, IgM is elevated, but short-lived. For IgG, titers 1:64 or less do not indicate active infection, titers between 1:64 and 1:256 suggest possible infection, and titers >1:256 suggest acute infection [71]. Testing for B. henselae infection can also be done by the polymerase chain reaction (PCR); commercial laboratories in the USA conducting this test on blood and tissue in 2020 are ARUP (Salt Lake City, UT, USA) and Quest Diagnostics (Secaucus, NJ, USA). CSD can also be diagnosed by lymph node biopsy with histopathologic exam and Warthin-Starry staining. However, the diagnosis of CSD by culture is impractical because of the slow growth of the organism [71].
Because of the diversity of etiologies of POGS and the difficulty of culturing many of the causative organism, universal (16S rRNA) PCR has been advocated and used successfully to determine the etiology of POGS [42]. The 16S rRNA test is commercially available through the University of Washington Laboratories (Seattle, WA, USA) using frozen tissue specimens, paraffin-embedded tissues, or body fluids. Although there are usually no long-term ocular sequelae if POGS is properly diagnosed, it still may cause weeks of ocular discomfort and necessitate multiple physician contacts.
Various criteria are used to define a confirmed or probable case of FBT. Confirmed cases were defined as a clinically compatible illness with one of the following serologic findings: ≥4-fold rise in antibody titer by IFA between acute and convalescent specimens; or a single IgM or IgG titer of ≥1024 in the endemic area. Probable cases were defined as a clinically compatible illness and a single serologic titer of ≥128 by IFA [72]. The R. typhi titers obtained for this patient were IgM >1:256 and IgG was 1:128. The illness was clinically compatible because of presentation with fever, headache, rash, and myalgias; elevated transaminases and lactate dehydrogenase levels; hyponatremia; hypoalbuminemia; thrombocytopenia; lack of responsiveness to beta-lactam treatment; and rapid response to doxycycline. Therefore, this would be defined as a probable case.

Conclusions
Parinaud's oculoglandular syndrome should be suspected in patients presenting with unilateral conjunctivitis that is accompanied by regional lymphadenopathy. POGS is most commonly associated with B. henselae, but many other organisms have been implicated. POGS associated with FBT has been described in children, but this is the first case described in the literature in an adult patient, which was also accompanied by anterior uveitis. The patient described above had complete symptomatic resolution after 14 days of doxycycline. Transmission likely occurred in this case via manual inoculation after petting a household dog contaminated with feces from infected cat fleas. The diagnosis of FBT in our patient was made on the basis of compatible laboratory and clinical findings, probable flea exposure, positive immunofluorescence serologic tests, and negative laboratory studies for other etiological agents. Thus, R. typhi/R. felis should be considered in the differential diagnosis for POGS in endemic areas.