Abstract
We report on a 38-year-old male patient with disseminated gonococcal infection. Preceding the discharge diagnosis, the patient was treated regarding rheumatoid arthritis, which resulted in the deterioration of the patient's medical condition due to the immunomodulatory nature of the applied medication. The causative agent was identified by culturing joint puncture fluid inoculated into blood culture vials. Primary infection with the pathogen could not be pinpointed in terms of time, but on further questioning, the patient reported intimate contacts with a number of different male partners, which may be assumed to have included the infection source. The case hereby demonstrates the impact that an early misdiagnosis and a limited anamnesis can have on the progress of a patient's disease. Furthermore, this case has helped us to propose possible improvements in both clinical and microbiological diagnostic approaches.
Introduction
Neisseria gonorrhoeae are gram negative strictly aerobic diplococci and the causative agent of gonorrhea (see Fig. 1). With an estimated 82.4 million cases globally in 2020, it was the second most prevalent bacterial sexually transmitted disease (STD) worldwide and has significant prevalence in both developed and underdeveloped countries [1]. It was the second most reported STD in the European Union and mainly affects 15–25 year olds with humans being the only reservoir [2]. Infections by N. gonorrhoeae usually manifest at the mucous membrane site of infection, in males most often as urethritis with purulent efflux as well as inflammation of tissue in close proximity to the urethra, in females mainly as cervicitis, although, in both sexes symptoms may be absent [2]. Depending on sexual preferences, pharyngeal and anal infections may occur. Transmission during birth may lead to ocular gonorrhea [2]. The clinical signs of urethral gonorrhea are well known and enable a relatively precise visual diagnosis. Nevertheless, depending on the site of infection, symptoms can vary in their characteristics and aren't often as clear as is in the case of urethral gonorrhea or are even missing altogether: Besides pharyngeal, anal and ocular gonorrhea [2, 3], there are rare variants of this disease which are caused by systemic dissemination of bacteria resulting in e.g. hemorrhagic skin lesions as well as tenosynovitis, purulent arthritic joint infections and migratory polyarthritis. Even osteomyelitis, meningitis and endocarditis can occur [4]. These are often misdiagnosed and thus pose a risk of ineffective treatment. Just how many cases of disseminated gonococcal infections (DGI) there are in total is hard to pinpoint because of the inconsistent legal situations regarding the obligation to report infections. However, it is estimated that around 0.4–3% of all infections by N. gonorrhoeae, develop into a DGI [4].
Upscaled image of a gram stain of the patient's N. gonorrhoeae strain. Note the kidney-shaped diplococci configuration which is typical for N. gonorrhoeae
Citation: European Journal of Microbiology and Immunology 13, 1; 10.1556/1886.2023.00004
Case description
In August 2022, a 38-year-old male patient was hospitalized in one of the orthopedic wards of the university hospital Bonn, presenting with suspicion of a ruptured Baker's cyst. The afore-mentioned Baker's cyst had been punctured four days previously and microbiological samples had been obtained for diagnostics. In the processing of the sample, we were able to isolate N. gonorrhoeae via enrichment in blood culture vials (Becton Dickinson, Franklin Lakes, United States). The alleged Baker's cyst initially hadn't been the cause of the patient's complaints. Prior to the current hospitalization and identification of the triggering agent, the patient had complained of swollen joints, namely his right wrist, hand and fingers, which had first appeared 3 months earlier. The patient had then immediately been to see his general practitioner who suggested a tendovaginitis and treated the affected joints with bandages and anti-inflammatory ointment. One day after the onset of the first symptoms, his ailment had progressed resulting in the swelling of his left wrist, hand and fingers. Another day later, fever of 40.5 °C had added to his discomfort and the patient had presented in the emergency room of a peripheral hospital. There the suspected diagnosis was maintained and the treatment remained unchanged. As his fever continued together with night sweats, the patient's right knee joint began to swell and pain. Another day later, the patient's left shoulder started to ache under subtle swelling resulting in impaired mobility. Following the deterioration of the patient's condition, the general practitioner suggested an examination in an emergency room. Initial general internal examination could not detect any conspicuous results; the flushed, edematous, painful joints, some of which were very warm to the touch, led to rheumatologic examination. Laboratory parameters showed a strikingly high C-reactive protein (CRP) (214.2 mg l−1; reference value: 0–3 mg l−1), whereas the rheumatoid factor was only slightly elevated (18.1 IU ml−1; reference value: <14 IU ml−1). Diagnostic aspiration of the affected knee joint showed 112,200 leucocytes/µl. Unfortunately, direct microbiological culture of the sample did not show any growth of bacteria on either Columbia blood agar or on chocolate blood agar incubated in a 5% CO2 atmosphere, possibly due to the sensitive nature of N. gonorrhoeae in terms of cultivability and survivability. Microscopic examination of the material was not conspicuous either. As a result, the diagnosis of anticyclic-citrullinated-peptide-negative, rheumatoid-factor-positive rheumatoid arthritis was made. An ongoing anti-rheumatic treatment with prednisolone (100 mg d−1 for the first two days, followed by 500 mg d−1 for three days, then gradual reduction) had already been applied on the first day of hospitalization. Additionally, long-term treatment with methotrexate (initially with 20 mg/week, reduction to 15 mg/week after one month of treatment) and folic acid (5 mg after application of methotrexate) was established. Most of the patient's complaints were regressive over time. However, he continued to complain of severe pain in his left shoulder accompanied by almost total mobile impairment and some of the other afore-mentioned joints still being slightly swollen as well as being slightly painful. The concentration of CRP was decreasing but still massively elevated (141.25 mg l−1). An immunomodulatory therapy was further intensified. Approximately four weeks after the onset, complaints relating to the patient's shoulder improved with respect to pain and mobility, the patient's right knee was still swollen and a sensation of tension had developed tending towards the medial knee cleft. Additionally, a new swelling of the right upper ankle joint had appeared. Probably due to the effects of the patient's medication, common side-effects like hypertonia and candida esophagitis had appeared. In a joint sonography of the right knee in August 2022, an accumulation of liquid regarding a ruptured Baker's cyst could be seen. This finding resulted in surgical treatment (arthroscopy, debridement, sample collection and rinsing) of the knee joint, the Baker's cyst as well as the left shoulder joint. The collected samples were incubated in blood culture vials and after two days of incubation, growth of bacteria in the samples of the knee joint and Baker's cyst was detected. Microscopy clearly showed typical kidney-shaped gram negative diplococci. Identification via matrix-assisted laser desorption ionization time-of-flight mass spectrometry confirmed that the bacteria indeed belonged to the species N. gonorrhoeae. We determined the antibiogram via epsilometer test, which showed that this strain was in fact resistant to azithromycin (see Table 1). Native samples that had not been previously incubated in blood culture vials failed to detect bacteria: Neither direct culture, nor culturing in enrichment broth, nor the assay with the Curetis Implant & Tissue Infection nucleic acid amplification panel (Curetis GmbH, Holzgerlingen, Germany) could provide any evidence. It has to be clarified, however, that the latter method is not designed for the detection of bacteria of the genus Neisseria. Three triplets of regular blood cultures collected in May 2022 failed to grow any bacteria. Upon discovery of the infectious agent, a specific anamnesis was undertaken and it turned out that the patient had performed male-to-male sex with mechanical protection by condoms only for anal intercourse and not for fellatio in a time period which fits the hypothetical time point of infection. As these findings were congruent and matched the diagnosis of gonococcal arthritis, antibiotic treatment with ceftriaxone for seven days was initiated. We performed follow-up testing on STDs in August 2022, which, unsurprisingly, turned out to be negative, most probably due to the self-limitation of the disease or at the very least antibiotic treatment. The patient did not report any symptoms of gonorrhea, so he has to be regarded as a patient with no obvious symptoms at the site of primary infection [2–5]. We decided to test the cryopreserved joint aspiration samples, which had been collected during both the patient's first and most recent stay, via off-label use of polymerase chain reaction (PCR) for the detection of STDs, and we were able to detect N. gonorrhoeae in samples gathered as early as during the patient's first hospitalization. However, the proof of N. gonorrhoeae only succeeded in samples of knee joint aspiration and Baker's cyst aspiration, whereas samples were negative for the left shoulder joint. To the best of our knowledge, this would also be the first documented proof of N. gonorrhoeae in a Baker's cyst. In summary, this course of disease was most likely initiated by transmission of N. gonorrhoeae during male-to-male sexual oral transmission leading to a pharyngeal gonorrhea, which then disseminated to the patient's joints. The misdiagnosis of rheumatoid arthritis led to an immunomodulatory treatment that might have had detrimental effects on the patient's immune response to the infection. Treatment may have helped the bacteria to further disseminate to the other joints which were affected, which is also supported by the patient's progressive clinical symptoms. Laboratory parameters couldn't provide clear evidence of autoimmune disease. Unfortunately, the first joint aspiration in May 2022 initially showed no growth of bacteria, probably because of the bacteria's sensitive nature, and therefore the first suspected diagnosis continued to be pursued. Nevertheless, the presence of a high count of leucocytes should have made the treating staff suspect that there was an infectious cause after all. It wasn't until the treating surgeon decided to collect aspiration samples in a blood culture vial that the causing agent could be identified which was the game changer for this case.
Antibiogram of Neisseria gonorrhoeae found in the patient's sample (aspiration of patient's right knee joint in August 2022). Susceptibility categories are interpreted according to EUCAST breakpoint tables (version 12.0, 2022) [14]. Note that usually susceptibility category of penicillin-G is not reported and benzylpenicillin should not be used for treatment of gonorrhea
| Substance | Minimal inhibitory concentration in mg l−1 | Susceptibility category |
| Penicillin-G | 0.25 | Susceptible, increased exposure |
| Ceftriaxone | 0.003125 | Susceptible |
| Meropenem | 0.0125 | Insufficient evidence |
| Tetracycline | 0.375 | Susceptible |
| Azithromycin | 3.0 | Resistant |
| Ciprofloxacin | 2.0 | Resistant |
Discussion
This case in particular once again demonstrates what effect the confusion of infectious and autoimmune origin of a disease can have on the progression of complaints and overall outcome. This is a commonly encountered “putting-all-your-eggs-in-one-basket scenario” many physicians have experienced, its greatest significance being in the field of transplantation medicine. Gonorrhea is a well-known infectious sexually transmitted disease with increasing prevalence [6]. However, DGI do not appear so frequently that they are often taken into consideration by young physicians, nor do they appear so rarely that it is so very unlikely they be encountered from time to time. Taking this into consideration and given that infections with N. gonorrhoeae are not necessarily associated with symptoms, this culminates in the disadvantageous situation of simply overlooking a possible DGI, all highlighting the importance of lessons learned in this case: The absence of clinical symptoms of mucosal gonorrhea as well as a negative culture of the first knee joint aspiration led the medical staff to more or less exclude an infectious disease. A lack of symptoms at the initial infection site seems to be common in DGI and is frequently encountered [7–9]. An explanation could be that if there are symptoms of gonorrhea, patients are administered correct treatment early on, which, in turn, prevents systemic spread of the pathogen. Many case descriptions report on arthritis mainly of the patients' wrists, interphalangeal joints, ankles and elbows, and sometimes of the knee joints as well [7–10]. Which joints are affected, and in which combinations, can vary. In the case reports reviewed for this publication the wrists are the joints most commonly affected [8–11]. The affection of the shoulder joint as in our case, however, does not seem to be very common. Whether there is causality between the development of Baker's cyst and DGI could not be conclusively determined. A literature search in this regard remained inconclusive. Additionally, no typical skin lesions were apparent, which can usually be seen in around 75% of all so-called arthritis-dermatitis syndrome DGI, and would therefore be indicative [7]. Nevertheless there were several indications that pointed to an infectious origin in the described case: Firstly and most importantly, the patient's sexual anamnesis showing that the patient had performed partially unprotected male-to-male sexual intercourse with different partners, which is a well-known risk factor for an infection with N. gonorrhoeae [6]. This would have been easily obtainable information that could have led to the idea of a STD from early on. Another important piece of information that could have been gained was that the patient complained of fever, which is rather a sign of infection-triggered arthritis in the sense of either septic arthritis or rheumatoid fever rather than rheumatoid arthritis. In DGI, however, fever may fail to appear, especially in cases with purulent arthritis [7]. It has to be said that the little time and low cost required to perform anamnesis, as well as the value of the information gained, cannot emphasize enough the importance of this efficient diagnostic instrument. However, time and again, a sound and solid anamnesis had not been conducted in this case. Secondly, even though the first joint aspiration showed no cultural growth, the high count of neutrophilic granulocytes indicated that an infectious agent was present at the particular site of the sample collection. Laboratory parameters showed a strikingly high level of CRP further supporting an infective pathogen as the cause. The suspected diagnosis of rheumatoid arthritis is rather contradicted by the laboratory parameters. Dissemination of bacteria had occurred before the first application of immune modulatory therapy, which suggests that the patient had an asymptomatic pharyngeal gonorrhea, when taking the patient's history into account. Sadly, the incorrect initial diagnosis prolonged and may even have worsened the suffering of this patient. Published case reports show, however, that the initial treatment of gonococcal arthritis with immune suppressive medication due to mistaking gonococcal arthritis with autoimmune diseases, is not a rare exception. Also the initial improvement of complaints and the subsequent spread to other joints is congruent to our report [7]. The breakthrough in this case was the collection of knee joint aspiration in a blood culture vial. According to literature, neither direct cultures of synovial fluid samples and skin lesions, nor blood cultures are very sensitive detection tools [8, 9]. This is why their diagnostic value may be limited in cases caused by DGI. We also made this experience and therefore suggest sampling joint aspirate in blood culture vials. The collection of specimens from all exposed urogenital sites as well as extragenital sites, that is, including joint aspirates, but also including pharynx, anal region and skin lesions, is recommended by the Centers for Disease Control and Prevention of the United States [12]. We experienced that cultural and molecular biological proof of the pathogen on the site of initial infection may not be successful. However, vital bacterial material may still be present in a joint effusion caused by the pathogen. We hypothesize two particular reasons why the use of joint aspirate sampled in blood culture vials for the identification of gonococcal arthritis is superior to the direct cultivation of native samples: The most important factor is the time the bacteria spend in a favorable environment. Whereas native samples may be subjected to lengthy transport at room temperature, samples collected in blood culture vials are usually transported faster and incubation starts earlier. Secondly, there are fewer early working steps for blood culture samples. These factors make it possible for highly sensitive organisms such as N. gonorrhoeae to survive sample processing. According to Reimer et al. blood culture vials containing sodium polyanethole sulfonate (SPS) are not well suited for the cultivation of Neisseria spp. [13], which, nonetheless, worked well in our case. For the above reasons, we strongly recommend sampling joint aspirate in blood culture vials, preferably those enriched with gelatine or those in which SPS has been replaced by sodium amylosulfate, which supports the growth of Neisseria spp. [13].
Conclusion
The sensitivity of the pathogen, which requires transport media containing nutrients and transport at 35 °C for the best chances of a successful culture, as well as the important missing elements of anamnesis are the obvious reasons for the long path to the discharge diagnosis. We hereby conclude that in every case an all-encompassing anamnesis has to be performed. This diagnostic tool is often underestimated and the cost as well as the time required for anamnesis make it very efficient. Nevertheless, there don't necessarily have to be signs of gonorrhoea in the patient's history, as even asymptomatic cases or cases with neglectable symptoms can lead to systemic dissemination of the pathogen. The history of the patient's sexual behaviour, however, can be crucial. Even though there is often little time in the clinical context for example because of the high number of patients who require treatment with the result that anamnesis is often neglected, the physician should always take enough time to take a detailed medical history which should be recorded in as much detail as possible. A high neutrophilic granulocyte count in aspirates and an elevated serum CRP can be indicative and are to be considered critical instruments of diagnostics. The third lesson learned is that joint aspirates, besides being cultured directly, should always additionally be cultivated in blood culture vials to ensure that highly sensitive organisms can be detected. Last but not least, the use or development of multiplex-PCR-panels that include tools for the detection of N. gonorrhoeae in joint aspirates is preferable.
Funding sources
The authors received no external financial support for the research, authorship, and publication of this article.
Authors’ contribution
All authors were involved either diagnostically or therapeutically in the management of the patient and had full access to all data relevant to the case report. All authors planned, wrote and reviewed the manuscript together.
Conflict of interest
The authors declare no conflict of interest.
Ethics statement
Not applicable.
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