Objectives The objective of this retrospective study was to summarise the clinical manifestations of, and to analyse the incidence and risk factors of, Jarisch–Herxheimer reaction (JHR) during the treatment of children with symptomatic congenital syphilis.
Methods Clinical data of 60 children with clinically and laboratory diagnosed congenital syphilis, hospitalised in Beijing Ditan Hospital between January 2010 and November 2015, were collected and analysed.
Results A total of 11 patients with congenital syphilis (11/60, 18.3%) developed JHR. JHR occurred in 1–6 hour after the first dose of penicillin. Common clinical manifestations included fever (11/11, 100%), irritability (11/11, 100%), rapid pulse and breathing (11/11, 100%), exacerbation of existing rash (5/11, 45.6%) and chills (3/11, 27.3%). Of the 11 patients who developed JHR, 9 patients (9/11, 81.8%) had bone syphilis, 10 (10/11, 90.9%) had more than three organs affected by syphilis and 10 (10/11, 90.9%) had a high plasma concentration of rapid plasma reagin (RPR) (≥1:256); these percentages were significantly higher than in patients who had not developed JHR (p<0.05), suggesting that the occurrence of JHR was related to bone syphilis, having more than three organs affected by syphilis and a high plasma concentration of RPR.
Conclusions Clinicians should be familiar with the risk factors for this reaction and its common clinical manifestations.
- infectious diseases
- risk factors
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The incidence of syphilis has been significantly increasing in China, and, accordingly, the incidence of congenital syphilis has also increased at a worrisome rate.1
Jarisch–Herxheimer reaction (JHR) is a transient immunological reaction that often occurs during antimicrobial treatment of syphilis. Clinically, it manifests with short-term constitutional symptoms (fever, chills, headache, myalgia) and exacerbation of existing cutaneous lesions in adults with syphilis. Most often, JHR is harmless and self-limited; however, the patients and their relatives may be alarmed by the reaction and, on rare occasions, inexperienced doctors may confuse it with hypersensitivity to treatment, which could lead to inappropriate termination of the treatment. There are several systematic studies of the clinical manifestation, diagnosis, treatment, risk factors and incidence of JHR in the treatment of adult syphilis.2 3 However, few reports, mostly case reports and few reporting systematic research, are found about JHR in the treatment of congenital syphilis.
Therefore, in this retrospective study, we summarise the clinical manifestations and analyse the characteristics, incidence and risk factors of JHR occurring in children with symptomatic congenital syphilis treated at our hospital.
This was a retrospective study that had been approved by the Institutional Review Board of Beijing Ditan Hospital, Capital Medical University (approval number 2015-5-11B). Clinical data of all the children with clinically and laboratory diagnosed congenital syphilis, hospitalised in the Department of Paediatrics, Beijing Ditan Hospital, Capital Medical University, China, from 1 January 2010 to 31 November 2015 were reviewed. Sixty children including 34 males and 26 females, with a median age of 49 days (ranging from 1 day to 2.5 years), were enrolled. All these patients had received initial antisyphilis treatment in the hospital where this study was conducted, and in all cases other severe congenital and infectious diseases had been excluded. The data included basic demographics; clinical manifestations associated with syphilis infection, as well as JHR (in children with JHR); organ damage, as evaluated by clinical manifestations and by routine test or other special tests on blood, cerebrospinal fluid or urine samples, or by X-rays and type B ultrasound; rapid plasma reagin (RPR) level; Treponema pallidum particle agglutination; fluorescent treponemal antibody absorption (FTA-ABS) immunoglobulin M (IgM) titre; white blood cell count (WBC); C-reactive protein level and procalcitonin levels.
All the mothers of these children had latent syphilis without clinical symptoms and had not received antisyphilis treatment during pregnancy; they were diagnosed as having syphilis by positive RPR tests and T pallidum particle agglutination in serum. The diagnosis of symptomatic congenital syphilis was made according to published criteria.4 5 If a mother had syphilis infection during gestation, her child was diagnosed as having symptomatic congenital syphilis if the following criteria were fulfilled: presenting clinical manifestations or organ damage associated with syphilis infection and satisfying one of the following standards: (1) RPR level more than fourfold of that of the mother’s; (2) FTA-ABS- IgM positive; and (3) RPR or T pallidum particle agglutination persistently positive in children >18 months of age.
All the patients were treated with intravenous penicillin administration at a dosage of 50 000 U/kg body weight; every 12 hours if the patients were younger than 7 days, and every 8 hours for other patients. The course of treatment was 14 days.6 Moreover, symptomatic and supportive treatment was provided according to a patient’s clinical manifestation and organ damage. If a patient developed JHR, a dose of 0.1–0.3 mg/kg body weight of dexamethasone was administered for relief, without the need to withdraw penicillin.
All statistical analyses were performed using the statistical software SPSS V.13.0. Discrete data were described using percentages and continuous data were described using mean and SD. Comparison between groups was analysed using Student’s t test for measurement data of normal distribution, the Wilcoxon rank-sum test for measurement data of non-normal distribution and the χ2 test for discrete data.
The clinical manifestations of congenital syphilis included manifestations of the skin, the haematological system, liver, bone, central nervous system and kidney. JHR was observed in 11 patients (11/60, 18.3%). These patients developed JHR in 1–6 hours after the first dose of penicillin, manifested usually with fever (39.0–40.3°C), irritability, rapid breath and pulse, exacerbation of existing rash and chills. One patient with suspected pulmonary syphilis who developed JHR also manifested laboured breathing and hypoxaemia. Another child developed bloody stool without the above common manifestations; routine test of stool revealed 4–10 red blood cells per high power field and no WBC was found; stool culture and stool smear ruled out other infections. Thus, the most common clinical manifestations were fever (11/11, 100%), irritability (11/11, 100%), rapid pulse and breathing (11/11, 100%) and exacerbation of existing rash (5/11, 45.6%) (table 1). These symptoms disappeared within 0.5–3 hours after dexamethasone was administered.
As shown in table 1, the occurrence of JHR is related to bone syphilis, having more than three organs affected by syphilis, and a high plasma concentration of RPR. Of the 11 patients who developed JHR, 9 patients (9/11, 81.8%) had bone syphilis, 10 (10/11, 90.9%) had more than three organs affected and 10 (10/11, 90.9%) had a high plasma concentration of RPR (RPR ≥1:256), and the percentages were much higher than for patients who had not developed JHR (p<0.05). Statistical analysis also demonstrated that the occurrence of JHR was not related to sex, age, other organ damage, FTA-ABS-IgM, white blood cell count or levels of C-reactive protein or procalcitonin (p>0.05, some data not shown in table 1).
There is a paucity of clinical data about JHR among children, and many paediatricians might lack sufficient understanding of the clinical manifestations of this reaction in children. This study should help paediatricians in making more accurate and timely decisions in clinical practice.
According to a few case reports,7 8 clinical manifestations of JHR in children with congenital syphilis include high fever, irritability, rapid breathing and pulse, and exacerbation of existing rashes, similar to the findings of this study. An interesting finding of this study was that, apart from the common manifestations of JHR, one child developed bloody stool and one developed laboured breathing and hypoxaemia. Essentially, JHR is a worsening response of existing lesions to treatment, so bloody stool might be a worsening response of gastrointestinal tract syphilis, while laboured breathing and hypoxaemia might be a worsening response of lung syphilis. Previous studies demonstrated that the gastrointestinal tract and lungs could be involved in patients with congenital syphilis.5 9 In this study, a few patients were suspected of having lung and gastrointestinal tract syphilis based on their clinical symptoms; however, a definite diagnosis could not be made since no invasive procedures were performed. Thus, apart from common clinical manifestations, manifestations of JHR could be diverse, according to specific organ damage associated with syphilis.
Finally, it is paramount for paediatricians to distinguish JHR from drug reactions. In most cases, JHR occurred 1–6 hours after the first dose of penicillin, while allergic reaction to penicillin mostly occurred within the first hour following drug administration and could easily be distinguished from JHR. Moreover, the clinical manifestations of allergic reactions to penicillin are different. In contrast to the manifestations of JHR described in this paper, allergic reactions to penicillin may manifest as urticaria, laryngeal oedema, dyspnoea, increased heart rate, disturbance of consciousness and even shock.10 Paediatricians should be able to distinguish these symptoms to avoid inappropriate termination of treatment, and should also, before treatment, educate parents of these children to be wary of the likelihood of developing JHR, thereby avoiding potential disputes associated with probably JHR. This applies especially where children have risk factors of developing JHR, such as having more than three organs affected by syphilis, bone syphilis and a plasma concentration of RPR ≥1:256, according to the findings of this study.
Handling editor Khalil G Ghanem
Funding This study is an open project funded by Beijing Key Laboratory of Emerging Infectious Diseases (project number DTKF201503).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Institutional Review Board of Beijing Ditan Hospital, Capital Medical University (approval number 2015-5-11B).
Provenance and peer review Not commissioned; externally peer reviewed.