Original Article Sep 2012; Vol 22 (No 3), Pp: 319-325

Iran J Pediatr Original Article Sep 2012; Vol 22 (No 3), Pp: 319-325

Clinical Features and Long Term Prognosis of Childhood Brucellosis in Northeast Iran

Mohammad-Saeed Sasan*1, MD; Malihe Nateghi2, MD; Behrooz Bonyadi3, MD, and Mohammad-Hassan Aelami1, MD

1. Department of Pediatrics, Mashhad University of Medical Sciences, Mashhad, Iran 2. Imam Reza Hospital, Mashhad, Iran 3. Department of Pediatrics, Shiraz University of Medical Sciences, Namazi General Hospital, Shiraz, Iran Jul 01, 2011 Dec 16, 2011 Feb 12, 2012

Received: ; Final Revision: ; Accepted: Abstract Objective:

Brucellosis is a prevalent disorder in children of developing countries. The aim of this study is to describeMethods: the epidemiology and long term prognosis of Brucellosis in Khorasan, Iran. This is a descriptive cross sectional study (from November 2003 up to February 2006), the subjects of which are composed of 82 patients (from Imam Reza hospital, Mashhad, and Health Center of Kashmar). In this study the diagnosis of Brucellosis is based on serology accompanied with clinical signs and symptoms. Our strategy for duration of treatment was to treat all patients for at least 6 weeks. We followed the patients byFindings phone:and if necessary by visiting. During 38 months we had 82 children with Brucellosis. The mean age was 8.02 y, and 40% of them were girls (M/F=1.21). Summer with 45.9% of the cases was the peak season. History of consuming raw dairy products, close contact with farm animals, living in village and Brucellosis in family was found in 91.6%, 76%, 70.24% and 41.1% of the cases respectively. The presenting symptom in 79.7% of the cases was joint pain, 72.9% had history of fever during the course of the disease. Arthritis, splenomegaly and lymphadenopathy were found in 60.97%, 16.9%, 7.5%, of patients respectively. The therapeutic regimen of 48.7% of our patients was Co-trimoxazole and rifampin. We followed 74% of the patients for at least 3 years which showed the relapse rate of 6.5 %. There was a case of reinfection, a patient with residual sequel and one death related toConclusion:Brucellosis in our case series. Brucellosis is still a common disease in our children and at least a risk factor for it can be found in the history of almost all cases of pediatric Brucellosis. With at least six weeks treatment with two antibiotics and with close follow up, we can decrease the relapse rate in pediatric Brucellosis to zero, even without IranianrepeatingJournal theof Pediatrics serology, Volume during2 2or(Number after treatment.3), September 2012, Pages: 319-325

Key Words:

Brucellosis; Children; Prognosis; Epidemiology

Introduction Brucella melitensis B. melitensis is the main cause of human brucellosis. In endemic regions specialty when

Iran has been the second country[1] in the world for is prevalent, children account[2] for up to the prevalence of brucellosis . In our country 25% of cases of human brucellosis . According to * Corresponding Author; Address: E-mail: [email protected] Imam Reza Hospital, Mashhad, Iran

CDC case definition, in clinically and 15 y) with brucellosis who were visited by the epidemiologically compatible cases, brucellosis author (from January 2003 up to February 2006) can be confirmed by serology only when there is a in the Pediatric Infectious Diseases clinic or ward fourfold rise in Brucella agglutination titer between of Imam Reza hospital (Mashhad), and the second acute- and convalescent-phase (at least 2 weeks group is composed of 25 children from Kashmar

apart), otherwise in a symptomatic person a single[2] who were reported to the health center of the city titer of ≥160 is considered as a probable case , by different doctors from January 2004 up to but according to the Iranian national guideline for December 2005. Cases with simultaneous positive diagnosis of brucellosis (our cases are defined cultures with other organisms and cases with according to it), in symptomatic persons without incomplete data were excluded. previous history of brucellosis, Standard Tube In this study the diagnosis of brucellosis is based Agglutination titer(STA) ≥1/80Brucell a is abortous diagnostic for on serology (Wright ≥1/80, Coombs Wright brucellosis. This is because antigens which are used ≥1/80, 2ME≥1/40 and rose Bengal) accompanied in Wright STA test are (BA) with suggestive clinical signs and symptoms. antigens but brucellosisBrucellain melitensis Iran (like in other Our strategy for duration of treatment (in endemic countries in the Middle East) is almost Mashhad) was to treat all patients for at least 6 always caused by (BM). The weeks and/or 4 weeks after resolution of all signs agglutination of anti BM antibodies with BA and symptoms, without asking 2-Mercapto antigens is weaker than BA antigens and BA Ethanol (2ME) test before or after stopping antibodies agglutination, therefore many authors antibiotics. The Kashmar group was treated suggest that in endemic regions (in symptomatic according to national protocol for 8 weeks but we brucellosis persons without previous history of [3-9),] are not sure about the compliance of their STA titer ≥1/80 is diagnostic for brucellosis . patients. We followed the patients by phone and if The other reason for decreasing the cut off for necessary by visiting in clinic in November 2008. Wright test in endemic areas is the statics rule that says the Positive Predictive Value (PPV) of a test has direct relation with the prevalence of the disease in the population. Findings This article is a report of clinical features of children with brucellosis in Khorasan (Northeast Iran). The province Khorasane Razavi has 4,700,000 inhabitants, Mashhad (the capital of it) During 38 months (November 2003 up to is the second city of Iran with a population of December 2006) we had 82 children with 1,850,000. Kashmar is a city 250 km in south west brucellosis. The mean age was 8.02 y (10 m to 16 of Mashhad with 121000 inhabitants. In Khorasan y), the mean age of Kashmar and Mashhad group 38.8% of the population live in rural areas. was 9.7 y and 7.19 y respectively. Forty percent of According to the report of the health center of the the children were girls (M/F=1.21). Summer with Great Khorasan (2005) the incidence of human 45.9% of the cases was the peak season and brucellosis in the province was 3000-5000 cases winter with only 6.8% was the nadir. History of per year. drinking raw milk or having unpasteurized dairy products, direct contact with farm animals and brucellosis in family was found in 91.6% (55 of 60), 76% (19 of 25) and 41.1% (28 of 68) of the Subjects and Methods cases respectively, 70.2% of the cases were rural. We had three shepherds (7 to 16 years old) in our group. At least one of the above risk factors was This is a descriptive cross sectional study, the found in 98.73% (78 of 79) of the cases (Table 1). subjects of which are composed of 2 groups of The chief complaint of 79.7 % (67 of 84) of the patients, the first group consist of 59 children (0- cases was joint pain and/or limping. Fever Iran J Pediatr; Vol 22 (No 3); Sep 2012 321

Table 1:

Risk Factor Risk factors for brucellosis in our children Frequency Consumption of unpasteurized dairy products (n=60) Direct contact with farm animals (n=25) Brucellosis in family members (n=68) 55 (91.6%) Villager (n=74) 19 (76%) Any of the above risk factors (n=79) 28 (41.1%) 52(70.24%) 78 (98.73%)

accompanied with joint pain and/or limping was our patients was Co-trimoxazole and rifampin, the main presentation in 28 (32.9%) cases. Most seven (8.5%) cases received Doxycycline- (72.9%) of our patients had history of fever during Aminoglycoside for the first 2-3 weeks and then the course of their brucellosis, but only in 5% (4 of Doxy–rifampin, four cases got Co-trimoxazole, 84) fever was the chief complain and the dominant rifampin plus gentamicin for the first 2 weeks and picture of the disease (the typhoidal type of 2 cases were treated by Doxy plus rifampin. We brucellosis). Generalized lymphadenopathy, acute treated all patients for at least 6 weeks. flaccid paralysis and abdominal pain each Surgical intervention was done in 2 (2.3%) occurred in one patient as the chief complaint. patients (arthrotomy and hemicollectomy each in In physical examination arthritis, splenomegaly, one patient). The later was a 10 years old rural lymphadenopathy and vertebral osteomyeltis boy who was admitted in a local hospital with were seen in 60.97% (50 of 82), 16.9% (9 of 53), fever, bloody diarrhea and abdominal pain. He 7.5% (3 of 40) and 2.3% (2 of 82) of patients underwent laparotomy with diagnosis of respectively. Of 50 children who presented with appendicitis but the surgeon found patchy arthritis 36 (72%) had mono arthritis; knee (24 gangrenous lesions of right colon and right patients) and hip (23 cases) were the most hemicollectomy was done (which showed common involved joints (Table 2). nonspecific colitis in pathology), after surgery it Blood, Urine and joint fluid culture was done for was found that the serologic test for brucellosis is 12, 13 and 5 cases respectively and all of them positive (Wright 1/640, 2ME 1/640) and he was were negative, other laboratory findings of the treated for brucellosis. We followed the boy for 3 patients are shown in Table 3. years, he didn’t have any relapse of colitis (which The therapeutic regimen of 48.7% (40 of 82) of rules out inflammatory bowel diseases). Table 2:

Variable Clinical findings of brucellosis inTotalour chi numberldren = 84 Mean Age

Season 8.02 y (10m-16y) Male/Female ratio Summer 45.9% Chief Complaint Winter 6.8% 1.21 Joint pain (± Limping) 79.7% Fever + Joint pain (± Limping) (32.9%) Fever 5% (4 of 84) Generalized Lymphadenopathy 1 case Fever during the disorder Flaccid Paralysis 1 case Surgical Treatment Abdominal Pain 1case Relapse 72.9% Reinfection (Recurrence) 2 (2.3%) Persistent Sequels 4 (6.5%) Death 1 (1.6%) 1 (1.6%) 1 case (1.6%) 322 Prognosis of Childhood Brucellosis; MS Sasan, et al

Table 3:

Test Laboratory findings of children with brucellosisResult in Khorasan Platelet (mean) Thrombocytopenia (PLT<150000) 3 Hemoglobulin (mean) 291600/mm (13700-778000) WBC (mean) 8.1% (3 of 37) Leukocytosis (WBC>15000) 11.4gr/1003 (9-14.7) PMN>75% 8671/mm (3900-15700) ESR (mean) 2.3% ESR ≥50 mm/h 2.3% CRP 36mm/h (3-97mm/h) Normal inflammation markers 17.1% (6 of 35) (ESR and CRP and WBC) Negative in 46.1% 29.16%

WBC: White Blood Cell; PMN: Polymorphonuclear; ESR: Erythrocyte Sedimentation Rate; CRP: C-Reactive Protein

Discussion There was one death related to brucellosis in our cases. This was an 8 year old girl with sacroileitis who developed Drug-induced Hypersensitivity In Khorasan 38.8% of population live in rural Syndrome (DIHS). She presented with fever, areas but our study shows that 70.2% of children erythroderma, generalized lymph-adenopathy and with brucellosis are village residents, in Greece

hepatosplenomegaly at the third week of and Turkey too, most[ 10,11cases] of pediatric brucellosis treatment for brucellosis (with Co-trimoxasole are from rural areas . This is a sign of partial and rifampicin). She was admitted for DIHS, all the control of brucellosis in our country which is antibiotics were stopped and she was doing well mostly due to industrialization of dairies but at the 9th day of admission she suddenly production in the last decade. Now the great expired with clinical diagnosis of nosocomial majority of dairy products in the cities are from septic shock. modern automatic dairy factories which are under We followed 74.39% (61 of 82) of the patients strict control by health system. In rural areas of for at least 3 years (and up to 6 years) after the Khorasan people usually boil the milk before use treatment, four (6.5%) of them experienced but drinking fresh milk is not rare and especially relapse within 3 moths after the first treatment. cheese is made from raw milk. In highly endemic All of the relapses were in Kashmar group. Thus situations where non pasteurized dairy products the relapse rate in Kashmar group was 16% and in are prevalent in cities, there is not a predominance

Mashhad 0%. One of the relapse cases was a 15 of rural people among brucellosis cases[12 ]and even year old boy in whom relapse was in the form of the majority of cases are city residents . orchioepididymitis. Of 61 cases with long term Pediatric brucellosis is a perennial disorder, and

follow up only one (1.6%) case had residual seasonal prevalence of brucellosis[1,13-15] has not been sequelae due to brucellosis. She is a 13 year old noticed by many authors but some authors

girl who presented with acute flaccid paralysis in (similar to us) have shown that the[16,17,18,19,20,21 disorder is] 2002 (at age of 7 years) and was discharged with more common in spring and summer . the final diagnosis of brucellosis complicated with In these seasons un-pasteurized dairy products Guillain-Barre disease. After 6 years of follow up at from sheep and goats can be found in local October 2008 she walks to school independently bazaars. The seasonal prevalence is more obvious but she has some degree of residual weakness. for brucellosis from sheep and goat than from There was one case of recurrence or reinfection cows, possibly because of the longer lactation (brucellosis after more than 3 months of the first period in cattle. treatment) in our group which happened four Unlike adult brucellosis which is more like an years after the first episode of brucellosis. occupational disorder and has a strong male Iran J Pediatr; Vol 22 (No 3); Sep 2012 323

predominance, pediatric brucellosis is mostly a The relapse rate in pediatric brucellosis is food borne[16,17,22 disease-24] with no significant sex between zero to 85% depending on antibiotic dominance . The case series of pediatric regimen [17,22,25,26] (type of antibiotics and duration of brucellosis which have reported a strong male therapy) . No relapse has been reported predominance (m/f=3) have a high proportion with TMP-SMX and rifampicin (8-12 weeks) plus

(>40%) of young shepherds in them and hence[26] streptomycin (3 weeks) and with Doxycycline their m/f ratio is like an occupational disorder . +rifampicin for six weeks+gentamicin for 5-7 days.

There is only one case series of pediatric Relapse rate of 85% has occurred[ 12,26 with] two brucellosis[25] which has shown female predo- antibiotics for less than 3 weeks . With minance . treatment regimens of 6 weeks and in patients

The classic risk factors for pediatric brucellosis with mean age of seven years[11,12,25 (1-9] y), like ours, the are consumption of unpasteurized dairy products relapse rate is 7.4%-8.1% . The main cause and direct contact with farm animals. Sofian in a of relapse is premature stopping of medicines due report from Iran has shown that positive family to inappropriate regimens or patient incompliance history for brucellosis is the most important and and almost always the relapse can be treated specific predictor for pediatric brucellosis and successfully[1,17, with25] the same regimen but longer they have recommended to screen family[27] duration We couldn’t find any connection members of every patient with brucellosis . between age, clinical presentation and the Wright History of brucellosis in first degree families has titer with relapse rate in our case group. The great been reported in 15.6%[11,12 ] to 47% of pediatric disparity of relapse rate between Mashhad and brucellosis case series . Absence of any risk Kashmar group in our study may be referred to factor for brucellosis has been reported in 1.3% to more frequent re exposure to contaminated dairy 9.6% of pediatric brucellosis cases. This rate is product (and hence reinfection) and also less 1.2% in our study, therefore the Negative compliance with the medicines in rural Predictive Value( NPV) of absence of any risk communities in comparison to the city.

[factor,10,25,26] for diagnosis of pediatric brucellosis is high Most authors do not recommend serologic test . before stopping medicines (as a guide for

Although in developed countries brucellosis[1,16,22is] termination of the therapy)[1,13-15,18] or after it (for early mainly a disorder of immigrated minorities , detection of relapse) , but the opinion of a in our case series we had only one (1.5%) Afghan few authors is that serologic follow up can be used refugee which shows that the disease is still to show the patient response to therapy and after[28] endemic in Iranian population. ending of therapy for early detection of relapse . The typical clinical presentation of pediatric In our country some of the experts do not stop the brucellosis is joint complaint (limping, arthralgia, medicines until they have a negative or low arthritis) accompanied with fever, the prevalence (<1/40) 2ME test and some of them (like us) of these has been reported 41%-85%[22 -26 and] 73%- prefer to treat all patients for at least 6 weeks and 91% respectively in different reports . after at least one month of being asymptomatic, Screening tests for inflammation (CRP, CBC, ESR) discontinue it without any serologic follow up. are not very helpful in the diagnosis of pediatric Absence of any relapse in the Mashhad group of brucellosis, sever leukocytosis (WBC >20500) and our study which were treated according to the very high [ ESR10,17, 22 (>100)] almost never occur in latter strategy makes it more acceptable. Navarro brucellosis . Normal CRP is very common, and colleagues followed brucellosis patients after

WBC is normal or almost normal in most patients[13,22] treatment completion with quantitative PCR (Q- and ESR is normal or moderately increased . PCR) and found that many asymptomatic patients In endemic regions when a child with a systemic had positive Q-PCR at the cessation of therapy and illness has no abnormal screening test of during follow-up without experiencing relapse. inflammation, brucellosis is a good differential They concluded that a positive Q-PCR from diagnosis (as it was seen in 29% of the cases in an asymptomatic patient, recently treated our study). with appropriate antibiotic does not necessarily 324 Prognosis of Childhood Brucellosis; MS Sasan, et al

[28] warrant further treatment . 2. Case definitions for infectious conditions under public health surveillance. Centers for Disease Brucellosis is rarely a killing disorder in Control and Prevention. MMWR Recomm Rep. children. In adults although the mortality is low, 1997;46(RR-10):1-55.

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