Dilated cardiomyopathy is the most common indication for paediatric cardiac transplant (60%). Reference Inayat, Mahboob, Ali, Bokhari and Ashraf1 Patients who are candidates for heart transplantation are on the long waiting list because of the small number of organ donations and also it is a time-consuming process. On the other hand, transplantation requires immunosuppressive conditions, which exposes the patients to a wide range of infectious pathogens. Moreover, pre-transplant infections increase the chances of transplant rejection in transplant recipients.
Brucellosis is a common zoonosis disease caused by aerobic gram-negative coccobacillus called Brucella. Reference Tuon, Gondolfo and Cerchiari2 Iran, along with five other Eastern Mediterranean countries, has had more than 90,000 patients with brucellosis. Reference Noormal, Eltayeb and Al Nsour3 Continued traditional animal husbandry methods and other factors such as eating habits, personal and environmental health issues, and the preparation process of milk have resulted in the endemic of this disease in our country. Reference Noormal, Eltayeb and Al Nsour3 Brucellosis is a rare infection in transplant recipients, specify after transplantation if that was the case of bone marrow, Reference Ertem, Kürekçi, Aysev, Ünal and Ikincioğulları4 liver, Reference Islek, Sayar, Yilmaz, Günseren and Artan5,Reference Polat, Tosun, Ertekin, Aydinli and Emre6 and one case of cardiac transplant, Reference Nair, Appukuttan, Narayan and Nair7 but it has not been reported in children candidates for cardiac transplant so far. This study addresses two children awaiting cardiac transplant infected with brucellosis, one of them had a positive blood culture and discusses the management of paediatric treatment and preparation for transplantation.
Case presentation
The first case was a 13-year-old with dilated cardiomyopathy female (on the waiting list for cardiac transplantation), who has been referred to Shahid Rajaei Heart Center in Tehran, Iran, in May, 2017 with fever, arthralgia, diffuse abdominal pain, headache, night sweats, fatigue, and lassitude. She had no cardiac symptoms such as chest pain and dyspnoea but had anaemia and high quantitative C-reactive protein. Due to the persistence of symptoms, positive history of exposure to animals, and ingestion of unpasteurised dairy products, we studied some probabilities for brucellosis. The serum agglutination test was 1.320 and immunoglobulin IgM and IgG antibodies against brucella were positive. The serum 2-mercaptoethanol was also positive. She had a negative blood culture for brucellosis. Due to the diagnosis of brucellosis, antibiotics were changed to rifampin, ciprofloxacin, and co-trimoxazole (trimethoprim-sulfamethoxazole). Symptoms disappeared in a few days, but the treatment was continued for 5 weeks in the hospital (according to the infectious disease consultation) to achieve negative IgM and then the serum agglutination test changed to 1.80. In addition, orthotopic cardiac transplantation was performed.
The immunoglobulin (Ig) M and Ig G antibodies against brucella lipopolysaccharide were checked by serum enzyme immunoassay. Every 2 months until 1 year and then it will be done every 6 months. The serum 2-mercaptoethanol was positive. The patient was discharged 6 weeks later. Due to immunosuppressive regimen, both IgM and serum agglutination test changed to positive values after transplantation that is specific for Brucellosis; therefore, rifampin and ciprofloxacin continued for 6 months and then discontinued due to negative IgM and serum agglutination test; however, co-trimoxazole was continued due to coverage of both pneumocystis carinii and Brucella. Now she is under follow-up for 12 months with stable clinical status and negative brucellosis IgM and serum agglutination test.
The second case was a 13-year-old with dilated cardiomyopathy female, who has been referred with the same symptoms to Shahid Rajaei Heart Center in Tehran, Iran, in December, 2018. The patient was a rural girl and had a positive history of exposure to animals and ingestion of unpasteurised dairy products. She had mild leukopenia and high quantitative C-reactive protein. She also had a positive blood culture for brucellosis. The serum agglutination test was 1.1280. The immunoglobulin IgM and IgG antibodies against Brucella lipopolysaccharide were positive. The serum 2-mercaptoethanol was positive. Therefore, we administered gentamicin, ciprofloxacin, and co-trimoxazole. After 3 weeks, brucellosis IgM and blood culture were changed to negative and serum agglutination titre was decreased to 1.160 but we decided to do emergency orthotopic cardiac transplantation according to acute heart decompensation. The patient was discharged 6 weeks later. After transplantation, both IgM and serum agglutination tests changed to positive values. Though we discontinued rifampin 6 months after transplantation, ciprofloxacin and co-trimoxazole are still administered because of low levels of positive brucella IgM and serum agglutination test titre. Both of them had no complications.
Discussion and conclusion
The main presentation of the disease in our cases was fever with an unknown origin. Qasim et al’s study included 153 Saudi children with Brucella, 80% of them had fever and mild symptoms. Reference Qasim, Alshuwaier and Alosaimi8 Moreover, Ghaly et al reported that 24% of children with Fever of Unknown Origin in Egypt are caused by brucellosis. Therefore, it is recommended that in the evaluation of patients transplanted with unknown fever, even if the symptoms do not imply brucellosis, we should think about this disease and perform the necessary tests. Blood culture in brucellosis could be positive between 15 and 70% depending on the conditions and incubation period. Reference Feigin, Cherry and Demmler9 Blood culture was positive in one of the patients. In this regard, Qasim et al obtained a positive blood culture in 34% of children with Brucella. Reference Qasim, Alshuwaier and Alosaimi8 Since diagnosis is confirmed by obtaining the germ of the causative agent, it is necessary to perform blood culture in all patients and, if possible, bone marrow culture and keep the sample for a long time (at least 30 days) or use BACTEC medium, if appropriate.
The patients were treated with two treatment regimens of co-trimoxazole, rifampin, and ciprofloxacin or co-trimoxazole and gentamicin and ciprofloxacin for 5 weeks before transplantation. Transplantation was performed after a negative serology, blood culture, and absence of symptoms. After transplantation, they were treated with ciprofloxacin-co-trimoxazole and rifampin-ciprofloxacin for 6 months. Follow-up did not show any recurrence in 12 months.
In the study conducted by Ertem et al, a bone marrow transplant donor with brucellosis underwent injectable gentamicin treatment for two weeks and oral doxycycline for 8 weeks. The transplant was performed after a negative serology, blood culture, and manifestation of symptoms. No recurrence was observed in transplant recipients and donors after 13 months. Reference Ertem, Kürekçi, Aysev, Ünal and Ikincioğulları4 Ting et al’s study reported a kidney transplant after 3 years with a diagnosis of brucellosis who was treated with minocycline, co-trimoxazole, and tigecycline for 3 months. The patient simultaneously received immunosuppressive drugs and no recurrence was found. Reference Ting, Ho and Sung10 A case study addressed a 51-year-old patient after 3 months of cardiac transplant and diagnosis of brucellosis who was treated with doxycycline and co-trioxamazole for 12 weeks. Reference Nair, Appukuttan, Narayan and Nair7 Treating brucella due to frequent recurrences, in particular, in the transplant population treated with immunosuppressive drugs is a challenge because of drug interferences between antibiotics and immunosuppressive drugs. Moreover, acute kidney damage has been observed in this combined regimen. On the other hand, there is no unit guideline for treating brucellosis in patients who are candidates for solid organ transplantation or even brucellosis in transplant recipients. This study recommends a thorough examination of all infections, regardless of transplant status, an accurate history, and reassessment of symptoms during the problem. We also suggest the follow-up period to be performed every 2 months in the first year of transplantation and after that, it can be every 6 months. I presume blood culture, and serology and symptoms need to be negative. Furthermore, our colleagues are recommended to consider an appropriate time for treating brucellosis after transplantation which is 6 months.
Acknowledgements
We thank our colleagues from Rajaie Cardiovascular Medical and Research Center CICU who provided insight and expertise that greatly assisted the research.
Financial support
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflicts of interest
None.
Ethical standards
This material is the authors’ original work, which has not been previously published elsewhere. The paper is not currently being considered for publication elsewhere. All sources used are properly disclosed (correct citation). Copying of text must be indicated as such by using quotation marks and giving proper reference. All authors have been personally and actively involved in this substantial work leading to the paper and will take public responsibility for its content.
