MEDITERRANEAN SPOTTED FEVER IN CHILDREN - COURSE OF ILLNESS

1. M. Pishmisheva-Infectious Diseases Ward- General Hospital in 2. M. Stoycheva-Department of Infectious Diseases- Sveti Georgi University Hospital in 3. N. Vatev- Departmennt of Hygiene, Ecologie and Epidemiologie, Medical University- Plovdiv 4. Georgi Popov – Department of InfectiousDiseases – Military Medical Academy-

Key words: early age; rash; black spot; spotted fever

The Mediterranean spotted fever (MSF), also known as Marseilles fever is a tick-transmitted rickettsiosis caused by Rickettsia conorii. The main carrier and host of the rickettsiosis is the dog tick Rhipicephalus sanguineus. MSF is common to Africa, the Middle East, Arabia and south Europe and especially to the Mediterranean countries. In the disease was registered in 1948 and existed until 1970 with a limited number of people taken ill. After a 24 year latent period, the disease began to manifest itself since 1993 with an annual increase in the number of the diseased in the endemic regions./1,2,11,13 / The newly-appeared, “old” rickettsiosis has some distinctive features- spreads more intensively, is active in more regions, the course of the disease is more severe- it causes damage to many organs and has higher mortality rate. The contemporary Marseilles fever has lost its professional character, is more common among the inhabitants of the cities and there is no age at which the

1 disease cannot be contracted- middle aged and elderly people fall ill as well as children. /8,9,12/ Age is an important factor which influences the clinical course of the disease and also determines some special features of this course. With reference to this fact it is the objective of this research to analyze the clinical pattern of the Mediterranean spotted fever in children. Materials and methods For the time span from 1995 until 2012, 1510 patients who were diagnosed with Marseilles fever have been treated in the Infectious diseases ward in the General hospital in Pazardzhik. 257 among them were children from the ages of 0 to 18, which comprises 17,02%. The distribution according to sex, age and residence is presented in Tables 1 and 2.

Table 1. Table 2. .

AGE/ YEARS ALL BOYS GIRLS 0-1 3 1 2 1-4 9 4 5 4-7 77 39 38 7-14 86 44 42 14-18 82 45 37 257 133 124

CITY 52% VILLAGE 48%

2 The data confirms the tendency from recent years- more people in the urban areas fall ill. The towns from the district which are most affected are Septemvri and Pazardzhik. While analyzing the data there have been employed the methods of clinical observation, routine laboratory tests, patients’ medical history of the current disease as well as epidemiological history- endemic region, tick bite, presence of pets at home and other possible mechanism for contracting. The diagnosis was confirmed by the test for Indirect Immunofluorescence Microscopy in laboratory in the Military Medical Academy in Sofia. Among 257 children, the diagnosis was serologically confirmed in 228 of the cases, that is 88,7 %. The Marseilles fever has distinctive clinical symptoms. /7,10/. The basic symptoms for diagnosing are the following: 1. spring and summertime distribution- from the months of April until October. Table 3 shows the seasonal distribution.

Table 3.

2.Onset with febrility and infectious intoxication 3.Craniopharyngeal syndrome

3 4.Primary lesion-Tache noire de Pieri 5. Rash

Results

1. Incubation period- it was established among 89 of the children- 34,6 %. These are the children whose parents report a tick bite or other exposure to a tick. What makes an impression here is that such patients constitute just one third of the whole lot. It is necessary to ask the children for taking part in activities which presuppose tick exposure, that is, children love playing with animals, especially dogs. They should be also asked about presence of other pets at home or in neighbouring yards, playing in streets, lawns and gardens where animals might pass. The difficulties in determining the precise incubation period result from the fact that the tick bite does not cause pain and remains unnoticed. The average incubation period was established to be of 3,2 days. The longest period was 14 days and the shortest- just one day.

2. Severe onset - There was a severe onset of the disease in all of the 257 children who were previously in good health and showed no prodrome of the disease. 3. Toxic infectious syndrome - a/ Febrility -one of the basis symptoms of the disease. It was established in 254 of the children- 98,8%. The other didn’t have high temperature according to their relatives, or become febrile during their stay at the hospital. The average period of febrility after the commencement of the etiological treatment is 2,5 days which is a day and a half shorter than the same period in adults- 3,8 days.

4 Table 4 shows the temperature values. It is evident that in 57,5 % -146 children the temperature rises to 39 C, in 27,5 %- 70 children the values are above 39 C and in 14,8 %- 38 children-up to 38 C. b/ fever - this is a symptom which accompanies the temperature rise in two thirds of the adult patients and rarely in children- it was observed in 96 children over three years of age- 37,3 % /14,17/. c/ myalgias and arthralgias - most common in adults and much rare in children- 40 % or 103 children from which only four were from the age range 3 to 7, the others were over 7. Children most often complain from pains in the lower extremities, especially in the calves. In young children this manifests itself in a refusal to walk and wish to be carried by others. The other complaints are for muscle pains in the upper extremities, especially in the armpits and shoulders. Those pains are not as severe as in adults. Nevertheless one of the children experienced such acute pains that he was lying motionless and felt fear and pain with every touch d/ headache- this symptom is very common in adult patients- 62 % and rare in children- 8 %. It is characteristic of the more severe cases of the disease. It is localized at the front of the head –both in children and adults and usually passes for three to four days. /1,3,4,13/

5 e/asthenia and adynamia- The most persistent symptom in adults- it continues for more than a month after discharge / 1,2,3,4,6,8/ and is observed in 74,5 % of them. The patents over 65 years of age are all affected by it. In comparison these symptoms are evident in 8,9 % - 23 of the children. Only 2 of them are over 7 years of age. 16 are aged between 4 and 7. It is difficult to assess this symptom in young children. Three of the children wanted to be carried by hands all the time and they lay flaccid in their mothers’ arms. The other two preferred to lay undisturbed in their hospital beds. They would start crying if any contact was made. In adults this symptom affects two thirds of the patients whereas with children it has short duration which does not extend the hospital stay.

4.Craniopharyngeal syndrome - Complete craniopharyngeal syndrome is rarely observed in 19,5 % of all patients. Probably this is due to the fact that the patients are admitted to the hospital days after the onset of the disease in which period the syndrome might have already disappeared. In children of maximum seven years of age the syndrome has never been observed whereas in the group of over seven year olds the percentage is 13,6% or 35 children. Hyperemic and swollen uvula is most frequently observed as well as redness of the sclera.

5. Primary lesion-Tache Noire de Pieri - It usually manifests itself as a black ulcerous crust. It was observed in 187 of the 257 children, that is in 72,7 %. It might be seen anywhere. For instance, in almost half of the patients- 87, it was in the shoulder area- the hairy part of the head, the earlobe and the back of the head. Most likely this is associated with the fact that children play in the grass and in summertime they spend more time playing outside. Younger children with “tache noire” usually have pets outside the house or at home. Most frequently it is a single black spot, although that seven of the children had more than one, five had two spots and two had three spots. The children who had most spots, two were in the hairy part of the head and the third one on the shoulder and the neck.

6

6. Swelling of the lymph nodes - This symptom deserves special attention since it is very rarely observed in adults whereas common in children- 54 % or 139 children. /9,11,12/. Enlarged lymph nodes are generalized, their size ranges from that of a pea bean to an almond, they have soft consistency and do not cause pain during palpation. In the route of entry of the infection, there are observed lymph nodes which are enlarged and painful when palpated, which is the reason why parents start seeking medical help.

7. Rash - One of the basic symptoms of the disease. It was observed in all of the 257 patients- 100 % in children and and 98,2 % in adults. Typical for the disease is the papular rash which has given one of the names of the disease- Fievre boutoneus. The most frequent rash in our patients, both children and adults, was the maculopapular one- 78,9 %. Only 8,6 % had papular rash. The macular one was rarely observed. In its evolution the rash might become hemorrhagic, although that it is not necessarily associated with severe course of the disease but in the course of severe rickettsiosis the rash is almost certainly a hemorrhagic one. Two of the 1510 patients had a necrotic rash. One of them was a seven year-old child. In the adult patient there was a lethal outcome of the disease whereas in the child’s case it was a mild form of the illness. The number of the elements of the rash ranges, both in children and adults, from just a few to many macules and papules close to one another, which doesn’t always correlate with the severity of the disease.

Medical literature shows the places for the rash localization- in the body, the extremities (where it is more severe), palms, feet and face. 83,5 % of the adults patients had a rash on the palms and feet with only 27 children having rash on the abovementioned places. Face rash was observed in 65 adult patients and in 175- 68,1% children. Rash in the hairy part of the head hasn’t been observed- neither in children nor in adults, but it has been recorded by other researchers. /3,4,11/

7

Other symptoms: Hepatomegaly - Frequently observed symptom of the disease- 79 %. In over half of the cases there is an increase in the aminotransferase level. Children are no exception to this despite the fact that hepatomegaly and splenomegaly are more frequent among them. Both organs are enlarged to a medium extent only for a short time which is until the end of the first month from the onset of the illness. Profuse perspiration - Characteristic symptom of the illness- it is observed in 82 % of the adult patients but not in children. Other symptoms (less frequent) - As is the case with adults, children might experience nausea, vomiting, diarrhea, loss of appetite, runny nose and coughing.

8. Paraclinical status and complications

The paraclinical abnormalities in children are not different from those of the adult patients, but are considerably less frequent. The most common complications of the Marseilles fever which we observed were as follows: pneumonias, thrombophlebitis, meningitis, etc. Complications with children are rare and are characteristic of the more severe forms of the disease. In accordance with other researchers’ observations /1,3,4,6,8,11,12)/ , the severity of the illness increases with the advancement of age. The criteria for mild, medium-severity and severe forms of the disease are recorded in medical literature and none of the criteria taken by itself can be indicative of the severity of the illness. /4,11/.

According to our observation, 62,3 % of the children /160/ suffered from the mild form of the disease characterized by short-term febrility, relatively good health condition, insignificant damage to the organs and systems in the body. 35 % of the children /90/ suffered from medium-severity form of the illness expressed by high temperature values, prolonged febrile period, deteriorated

8 health condition, paraclinical abnormalities such as leukocytosis or leukopenia, thrombocytopenia, anemia, level of cytolytic enzymes three times above normal as well as electrolyte imbalance. In the remaining 2,7 % the disease was in its most severe form- long febrile period prior to hospital admission, extensively damaged health condition manifested by a syndrome of severe intoxication- the patients are pale and flaccid, they suffer from acetonemia, headache, their consciousness is disturbed,/6/ they may become comatose or experience seizures.

9. Treatment

The medicine of choice in the cases of Marseilles fever is vibramycin. The treatment with tetracyclines in early age and infancy is not recommended unless there are vital indications to do so. Alternative antibiotics are chloramphenicol, macrolides. The latter were used in the treatment of our patients. In the severe cases of the illness the patients were treated with fluoroquinolones intravenously applied in combination with doxycycline. The medium duration of the treatment in the severe forms included 7 to 10 days of intravenous application of fluorquinolones followed by a 5 day course of oral administration of a certain drug. The latter period is extended to 7 days in the mild or medium-severity forms of the disease. In the children’s cases we had no lethal outcome of the disease.

10. Conclusions

Marseilles fever affects both children and adults. Generally speaking, the clinical course of the disease exhibits the same symptoms as the ones described when the disease was first registered. However, there are certain characteristics of the disease in the children’s cases which are the following:

- less severe toxic infectious syndrome

9 - more frequently observed “tache noire” which is manifested by a necrotic crust: the conjunctiva is less frequently the route of entry of the infection - in most cases the primary lesion is in the hairy part of the head as compared to adults - swollen lymph nodes and a rash on the face are more frequently observed as compared to a rash on the palms and feet. Rarely, in the severe cases there remains a pigmentation of the skin after the healing of the rash - complications are rarely observed - short convalescence period with lack of asthenia or adynamia;

In general, the course of the Mediterranean Spotted Fever in children is milder as compared to cases with adults. However, there are severe cases in which the disease causes damage to many organs.

Bibliography

1. Pishmisheva M; D. Mitov; E. Aleksandrov- Clinical and epidemiological characteristics of the number of people taken ill by Marseilles fever in the district of Pazardzhik in 1996; Infectious diseases magazine- issue No 1 2. Mitov D; M. Pishmisheva; B. Kamarinchev- Special features of the epidemiology and clinical manifestation of the Marseilles fever in the district of Pazardzhik- Microbiology and Virology symposium-1998 3. Angelov L; E. Aleksandrov; G. Genev- Infectious diseases in people in Bulgaria with centers of infection coming from nature 4. Popivanova N- Viral and bacterial tropical diseases 5. Aleksandrov E; B. Kamarinchev- Marseilles fever in Bulgaria 6. Pishmisheva M; G. Genev- Cases of Marseilles fever which included typhus symptoms- Infectious diseases magazine 7. Loban K. M- Rickettsiosis in humans 8. Pishmisheva M; D. Velkova- Mediterranean spotted fever in the district of Pazardzhik- Survey; National conference for infectious diseases, epidemiology and microbiology-2004

10 9. Pishmisheva M- The use of macrolides in the treatment of Marseilles fever- National conference of infectious diseases- 2001 10. Vaptzarov Iv- Observations regarding a small outbreak of Fievre boutoneus (Marseilles fever ) in the region of Plovdiv- Healthacare, issue 1, 1948; (101-135) 11. Popivanova N; Y. Baltadjiev- Mediterranean spotted fever (Marseilles fever) in Plovdiv town and Plovdiv region- Epidemiological and clinical characteristics of the disease- Cotemporary State of the Rickettsioses in the World and in Bulgaria-2007; (124-145) 12. Pishmisheva M- Mediterranean spotted fever in the region of Pazardzhik- symptoms, paraclinical indications and treatment; Special forms of Rickettsiosis; Contemporary State of the Rickettsioses in the World and in Bulgaria 2007; (114-124) 13. E. Alexandrov et al.- Marseilles Fever in Bulgaria- State and Problems, Contemporary State of the Rickettsioses in the World and in Bulgaria 2007 / 80-93/

11

12

13