Atypical form of cat scratch disease in immunocompetent patient

Introduction. Cat scratch disease (CSD) is an acute infectious disease with benign course caused by the bacteria Bartonella henselae. Clinically, it is usually manifested as regional lymphadenopathy and mild infective syndrome. Rare forms of the disease which usually occur in immunocompromised presons are: encephalitis, transverse myelitis, neuroretinitis, granulomatosus conjunctivitis, arthritis, hepatitis etc. Case report. We presented an atypical form of cat scratch disease in a young immunocompetent female person. The disease was manifested with prolonged fever, rash, purulent lymphadenitis and hepatitis. The diagnosis was based on characteristic patohystological finding and exclusion of the other causes of lymphadenopathy. The patient was treated by antibiotics for a few weeks, with surgical incision and drainage of the purulent lymphadenitis. Conclusion. Atypical forms of CSD could be an important differential-diagnostic problem, especially if there is no opportunity for serological confirmation of the disease.


Introduction
Cat scratch disease (CSD) is an acute infectious disease with benign course and good prognosis caused by Bartonella (B) henselae.It is the most frequent cause of chronic lymphadenopathy in children and adolescents 1 .B. henselae is a gram negative slow-growing, intracelullar bacteria which causes granulomatosus inflammation of the skin and regional lymph nodes [2][3][4][5][6] .The first case of CSD was described by Robert Debre in Paris in 1931, in a ten-year old boy with limphadenitis who was in contact with a cat, but B. henselae as causative agent was identified in 1985 2,4,7 .The illnes is classified in the group of zoonosis, since it is transmitted from cats or kittens, what is more frequent, during scratches, bites or licking 3 .CSD is registred all over the world, although there is no exact data about the prevalence, as is the case in our area.Seropositivity against B. henselae ranges from 3.1% to 61.6% in general population in some parts of the world, which shows that a small number of infected persons become sick 8,9 .It is registred about 22,000 patients with CSD per year in the USA and the incidence is 9.3 patients per 100,000 inhabitants 1,6,9,10 .The disease appears more frequently during automn and winter in temperate climate zones, most frequently in children and adolescents, so younger than 21 make 80% of all cases of CSD.Males suffer more than females 9 .
Incubation period is 1-2 weeks in 90% of patients (3-12  days).It is followed by papulopustular lesion on the bitten or scratched place (primary lesion), which lasts about 1-3 weeks.After that, in 90% of patients, characteristic regional lymphadenopathy is developed and is followed by mild fever, anorexy, nausea, fatigue or headache 1,2,7,11 .Truncal maculopapular rash apears rarely 12 .Lymph nodes are painful and suppurate in 25%-30% of cases.CSD is a self-limited disease with exellent prognosis even in a severe form of the disease.Recovery is spontaneous in 2-5 months, but immunocompromised persons can develop severe and potentialy life-threatening forms of the disease 13 .Atypical forms of the disease, without papula at the site of inoculation and visible regional lymphadenopathy are present in 10% of cases with CSD.They include: encephalitis with seizures, transverse myelitis, arthritis, neuroretinitis, granulomatosus conjunctivitis, aseptic meningitis, hepatitis, osteomyelitis, endocarditis, myocarditis, pneumonia, splenic abscess, hemolytic anemia, trombocytopenic purpura etc 2, 14-27 .These atypical forms of CSD could be misdiagnosed as other infectious process or neoplasma 7 .
The aim of this study was to show rare form of CSD with prolonged fever, purulent regional lymphadenitis, maculopapular rash and hepatitis in a young immunocompetent female person.

Case report
A 29-year-old female person was bitten by a kitten the third finger of her left hand on 12 June 2010.Three weeks later papulopustular lesion appeared on the bitten place.After about 6 weeks, her axillar lymph nodes became swollen and painful on palpation and a tumor formation appeared in the region of the left elbow on 24 July 2010.By the end of July, the patient became febrile, about 39°C, followed by extensive night sweets.In that period her lymph nodes were grouped into packages, followed by skin redness behind them and extreme palpatory tendreness.Laboratory analyses from that period are shown in Table 1.As causative agents were excluded hepatitis A, B and C viruses, Epstain-Barr virus and Cytomegalovirus.The therapy with ciprofloxacin 1,000 mg per day was initiated in the regional hospital with suspition on CSD, but maculopapular rash on truncus, limbs and face appeared after 10 days.Ciprofloxacin was changed with doxycycline in a daily dose of 200 mg and antialergic therapy was initiated by a dermatologist.Since the treatment did not lead to a significant improvement, the patient was admitted to the Clinic for Infectious and Tropical Disease, Military Medical Academy, Belgrade, on 18 August 2010.
At admission, the patient was subfebrile, pale, in good general condition, with the present crust on the bitten place and with rash in regression at the medial side of both forearms, which absolutely dissapeared after 7 days.In the region of the left axilla, a lymph node package was registred (Figure 1).It was painful on palpation and without signs of supuration.In the region of the medial side of the left elbow, a tumor formation of firmer consistency about 2 cm in diameter was noticed.Physical examinations of pharynx, lung and heart were normal; there was no hepatosplenomegaly.
Pathological laboratory analyses at admission are shown in Table 1.Using serological analyses, as causative agents were excluded Human Immunodeficiency Virus (HIV), Toxoplasma gondii, Francisella tularensis, Echinococcus granulosum and Toxocara canis.
Five distinct oval hypoechogenic formations which were partialy in block, localized deeply in the muscle medialy beside the chest wall were registrated by ultrasound.They seemed to be enlarged and altered lymph nodes.A heterogeneous formation 3 cm in diameter was noticed behind the left elbow, medialy in the muscle, which seemed to be "a parasitic change".Ultrasound examinations of the neck and abdomen were normal.
After admission, the therapy with doxycyclin was being conducted for 7 days when it was stopped.A biopsy of the change in the left elbow was performed (Figure 1).The cap-  In repeated ultrasound examination, 5 weeks after the first one, a lobular heterogeneous liquid collection was registred, 4 cm in diameter, without capsula.Beside it a reactive lymph node was noticed 12 mm large (Figure 2).There were no pathologic findings in the subcutaneous tissue and muscle of the left axilla.A spontaneous drainage of abscess collection happened at that time and the patient became afebrile, with elevated erythrocyte sedimentation rate (ESR), C reactive protein (CRP), fibrinogen and serum transaminases (Figure 3).On October 4 2010, surgical procedure, incision and drainage of abscess collection, was done and a necrotic lymph node in the left axilla was eliminated.Purulent content was obtained, with no growth on pathogenic bacteria or Mycobacterium tuberculosis.The antimicrobial therapy was definitely stopped on October 18 2010 when the patient was without symptoms and with absolutely normal physical examination.Laboratory findings performed at the end of October are shown in Table 1.Elevated serum transaminases and other normal biochemical findings were noticed in the middle of December, while total laboratory findings were normal only at the end of January 2011.

Discussion
CSD is an illness of children and youths under the age of 20 and is manifested as benign and self-limited lymphadenopathy caused by bacteria B. henselae 9,12 .According to Erik 2 the disease appears in patients younger than 21 in 80% of cases.The reason for this could be in the fact that children are in contact with cats and kittens more freqently, so it is more probable to be scratched or bitten.The incidence of disease is not known in our country and only sporadic cases are reported.
After the incubation period of 3-12 days, on the bitten or scratched place, papulopustular lesions appear in about 90% of patients which lasts about 1-3 weeks 2 .In the presented patient the lesions were present but they appeared a little bit latter, 3 weeks after the bite.The most impressive clinical sign of infection is regional lymphadenopathy and it is present in 80% of patients.In about 10% of inflammed lymph nodes, the skin behind them becomes red.After that they fluctuate, what is the sign of suppuration and it is followed by spontaneous drainage 10 .Erik 2 cites in his research that lyphadenopathy is manifested primary in axillar lymph nodes and that they suppurate in about 25%-30% of cases.According to the same author, in 50% of cases only one lymph node is changed, in 30% more lymph nodes from different part of the body are infected and in 20% of cases a few lymph nodes from the same region are infected.In the presented patient one cubital and a few axillar lymph nodes were changed.
Mild fever is present in 30%-60% of patients and usually lasts about 1-2 weeks 6 .The presented patient was febrile about 20 days with some epizodes of high fever.In the literature are described cases of systemic illness in immunocompetent persons which arise hematogeneously.These forms are characterized with long-lasting fever, hepatosplenomegaly, granulomatous hepatitis, abdominal pain, weight loss, headache, weakness and malaise 28 .The presented patient had prolonged fever and signs of hepatitis with values of serum transaminases which were multiple as high, but granulomatous lesions in liver were not detected by ultrasound, and other diagnostic procedures (MSCT and liver biopsy) were not performed.
Dermal manifestations of CSD are quite infrequent and appear in about 5% of patients.Eryhema nodosum, erythema multiforme, erythema marginatum and non-specific maculopapular, morbiliform or petechial rash have been described till now 29 .Dzelalija et al. 12 described a similar case to the case we presented, with maculopapular rash, purulent lymphadenitis, slightly elevated serum transaminases and parameters of inflammation.The presented patient had macu-Koji M, et al.Vojnosanit Pregl 2013; 70(1): 72-76.lopapular rash considered allergic manifestation, but the same was exluded later, with the reintroduction of ciprofloxacin in the therapy, in hospital settings.
Diagnostic criteria for CSD are characteristic clinical picture, positive epidemiological data, exclusion of other causes of lymphadenitis, morphological and histopathological examination of the biopted lymph nodes, serological confirmation by detecting specific serum antibodies using immunofluorescency methods and detection of B. henselae genom using PCR method 3,[30][31][32][33] .
Morphological examinations (US, CT, NMR) are of great importance for diagnosing CSD.Lymph nodes are visualised as round or ovoid masses in diameter of about 1-5 cm by ultrasound examination 34 .In about of patients it is affected only one or more lymph nodes from the same region (hand, neck or axilla).Affecting more different regions is a sign of multiple inoculations or dissemination of the disease.Disseminated form of the disease can be registred by finding granulomas in the liver and the spleen by ultrasound 3 .The presented patient showed some signs for disseminated form of the disease, but on ultrasound no granuloma was detected.
The causative agent is difficult to be isolated from the human tissue, but isolation and identification of the agent is important in the detection of the disease in animals 3 .Cultivation of the microorganism from tissue specimens requires special cicumstances and is possible in well-equiped laboratories 35 .In modest labs, using special paintings (Gram, hematoxilin-eosin, Ziehl-Neelsen, Warthin Starry etc), characteristic histopathological findings can indicate CSD by the characteristic shape of granuloma what was used for the diagnosis in the presented patient.According to data from the literature, the presence of B. henselae in lymph node specimens is more freqent in patients with supurative lymphadenitis (67%) comparing to patients with non-supurative lymphadenitis (22%) 10,33 .In our patient, although it was supurative lymphadenitis a causative agent is not proven using silver painting by the Warthin Starry method, probably because the patient had already started antimicrobial therapy.The most applied serologial method for detection of serum antibodies againest B. henselae is indirect immunofuorescency (IIF) 32 .Sensitivity of the method is 88% and specificity 97%, although they vary between labs, so sensitivity of the method ranges from less than 30% to 100% 10,35 .In our country, unfortunately, no reference laboratory performs serological diagnosis of CSD.
B. henselae is sensitive on macrolids, fluoroquinolones, tetracyclines, rifampicin and sulfametoxazol-trimethoprim 3 .However, antimicrobial therapy very often has no efect on the course of the disease.There is no consensus about antimicrobial therapy of CSD in immunocompetent person, nor on duration of therapy, and the need for therapy.The presented patient was treated with ciprofloxacin and tetracyclines for 9 weeks, but according to the clinical and laboratory monitoring we could not conclude that antimicrobial therapy had good effect on the course of the disease.

Conclusion
Atypical forms of CSD could be an important differential-diagnostic problem, especially if there is no opportunity for serologial confirmation of disease.

Fig. 1 -
Fig. 1 -Regional lymphadenitis in the patient with cat scratch disease

Fig. 2 -Fig. 3 -
Fig. 2 -Ultrasound of axillar lymph nodes in the patient with cat scratch disease