SIK ATEŞLENEN ÇOCUK Dr. Mustafa Bakır Marmara Üniversitesi Tıp Fakültesi Göztepe EAH, 22 Mart 2011

Tanımlar Rekürran/Periodik Ateş Düzenli/düzensiz aralıklarla ve normal vücut ısısı dönemleriyle birbirinden ayrılan ateş tekrarları Kaynağı bilinmeyen ateş (FUO) >3 hf süren ve 1 hf yoğun incelemeye rağmen tanısı belirsiz ateş Before I go into the literature and the confusion begins, I want to present a working definition that I propose we use – a sort of compromise between what is in the literature and what our consultants use – because I think it will help us keep clarity in the data I’m about to discuss. The main difference in our discussion between the two definitions is that recurrent/periodic fever is separated by periods of return to normal temperature whereas FUO is not. This is not hard and fast in the literature, as people sometimes incorporate recurrent/periodic fever into FUO, but I think this is an important distinction to make for our discussion today.

Rekürran Ateş John & Gilsdorf 2003 “ 6 aylık periyotta tanımlanmış bir hastalık olmaksızın en az 7 gün aralıklarla gelen ≥3 ateş atağı” So keeping our working definitions in mind, what does the literature say? Arbitrary definition by John and Gilsdorf 2002, the authors of the only review article on recurrent fevers in children, arbitrary definition of recurrent fever. Lots of numbers and specific time intervals determined arbitrarily.

Rekürran/Periyodik Ateş Long 2005 Rekürran Ateş “Ateş ve diğer belirti ve bulguların azalıp arttığı tek bir hastalık” Periyodik Ateş “Ateşin ana belirti olduğu tekrarlayan hastalık atakları; haftalar-aylar süren tam iyilik dönemleri. Ataklar düzenli veya düzensiz periyotlarla gelebilir” Sarah Long, a pediatric infection disease specialist, takes a different approach and defines recurrent and periodic fever a little differently. Here, she uses a return to normal in between periods of fever to distinguish between recurrent and periodic fever. Her definition of recurrent fever is a little more like our definition of FUO, and her definition of periodic fever matches better to our definition of recurrent fever. Her criteria for timing in between febrile episodes also differs from John and Gilsdorf. So you see, it seems that everyone uses slightly different criteria for each entity.

Kaynağı Bilinmeyen Ateş Petersdorf & Beeson 1961 “>3 hf süren, birkaç kez en az 38,3oC ölçülen, >1 hf süren yoğun incelemelere rağmen tanısı belirlenemeyen ateş” Finally, there is controversy over what the definition of FUO is too. An adult definition that has been extrapolated to children. There is no consensus in the literature as to time intervals or temperature needed to fulfill this diagnosis. “prolongation of fever without finding any cause, which is disturbing to the medical staff and causes anxiety for the family” may be a more useful working definition.”

Etyoloji “Nadir belirtilerle seyreden yaygın hastalıklar” İNFEKSİYON İnflamatuar/Otoimmün Tanımlanamamış (rekürran)/Neoplazma (FUO) Well with all these differences between the entities of recurrent fever and FUO, are there ANY similarities? Well, it turns out that the BROAD diagnostic categories causing both entities are similar. It is simply the specific diagnoses that differ. Infection is number one in both recurrent fevers and FUO by far, followed by inflammatory/autoimmune diagnoses. The third most common etiology differs between the two entities, with no diagnosis being more common in recurrent fever and neoplasms being more common in FUO. Common things being common, however, the literature reminds us that the cause of recurrent fevers/fevers of unknown origin are still most likely to be common disorders with uncommon presentations. This has implications before we go hunting for those really rare diseases that are in the differential for both entities.

Etyoloji Enfeksiyöz Otoimmün/ İnflamatuar Malign Tanısız Diğer McClung 1972 (n=99) 28% 14% 8% 11% 16% Pizzo et al. 1975 (n=100) 52% 20% 6% 12% 10% Feigen and Shearer 1976 (n=20) 35% 5% 30% Lohr and Hendley 1977 (n=54) 33% 21% 13% 19% 15% Problems, problems, and more problems. Looking to the literature for the rates of each of these categories as a cause of recurrent fevers is problematic because the literature is fraught with the same confusion over definitions as we described earlier, and many study samples include both those with recurrent fevers and fever of unknown origin. Above are the rates of each broad diagnostic category that likely better reflects the incidence of each etiology in FUO rather than recurrent fever because FUO patients were better represented in the studies that reported their numbers of constant versus recurrent fevers. Most didn’t even make this distinction however. There is no data in the literature looking only at truly recurrent fever. This is likely because this problem is dealt with by so many separate specialties after they are referred by primary care physicians, and therefore, no one has looked at this group as a whole after the diagnosis is made. This is the best available information we have however. We see in these older studies done in developed countries (USA) that… Miscellaneous category includes drug fever, factitious fever, habitual/familial fever, hypersensitivity states, hemoglobinopathies, and dehydration. Pizzo et al. included both constant fever and recurrent fevers in their patient population. No reference to how many patients in each group. Height, pattern, duration of fever did not correlate with diagnosis or severity of illness. Feigen and Shearer no mention of pattern of fever in FUO.

Etyoloji Etyoloji FUO (n=102) Etyoloji FUO (n=185) Ciftci et al. 2003 Pasic et al. 2006 Etyoloji FUO (n=102) İnfeksiyon 44.2% Kollajen vasküler 6.8% Malinite 11.7% Diğer. 24.5% Tanısız 12.8% Etyoloji FUO (n=185) İnfeksiyon 37.8% Otoimmün 12.9% Kawasaki hastalığı 6.4% Malinite 6.4% Diğer. 8.1% Tanısız 30% More recently in developing countries… Ciftci et al. 2003 Turkey – no mention of pattern of fevers Pasic et al. 2006 Serbia – no mention of pattern of fevers Of special note is that Kawasaki’s Disease is an important diagnosis not to miss in those with constant fever, although this is not the population we’re focusing on today.

Ayırıcı Tanı Ateş Aralıkları Rekürran Ateş Ayırıcı Tanı Ateş Aralıkları So now that we know what the broad categories causing recurrent fever are, what is the specific differential diagnosis for recurrent fevers? This is perhaps best divided into those entities that present at regularly recurring intervals and those that return at irregular intervals. Düzenli? Düzensiz?

Düzenli Aralıklı Ateş Hep düzenli aralık var Bazen düzenli aralık var PFAPA sendromu Siklik nötropeni “Relapsing fever” (Borrelia spp. Burgdorferri hariç) Tanımlanamamış sebep Bazen düzenli aralık var FMF Hiper-IgD sendromu, TRAPS Kriyopirin sendromları EBV infeksiyonu Fevers at regular intervals are the most helpful because the differential is short. These etiologies for fever occurring at regular intervals generally are well in between. Periodic fever, apthous stomatitis, pharyngitis, adenitis (PFAPA) – most common cause of regular interval, no long-term sequelae Cyclic neutropenia – spontaneous recovery without medical treatment Relapsing fever – potential mortality, ask about history of exposures to ticks/lice John and Gilsdorf 2002

PFAPA Periodic Fever Adenopathy Aphthous ulcers Pharyngitis genellikle 3-5 gün 3-4 hf arayla tekrarlar Aphthous ulcers Küçük, yüzeyel, hızla düzelir Pharyngitis + eksüda Adenopathy Servikal Genellikle bilateral ve kısa süreli Cilt, solunum, GI veya eklem tutulumu yok CRP, Lökosit, ESP çok yüksek It was characterized by a primary complaint of Fever, which was brief, recurring in a periodic, timely manner and save associated oral ulcers, pharyngitis, and adenopathy, was without more serious focal or systemic signs of illness. The aphthous ulcers have been noted to occur in 60-70% of cases in the United states. They are typically few to several, shallow and small, ( <5mm in diameter), short-lived (resolving) in 5-10 days, and show no predilection for specific mucosal locations as do herpangina Pharyngitis is more variable, with the presence or absence of exudate having no diagnostic implications Finally adenopathy, which is typically bilateral, rapid to appear and resolve, and typically discrete and non-fluctuant

Tanı Kriterleri Periyodik ateş başlangıcı < 5y ÜSYE Sx olmaması ve şunlardan >1 : Aftöz stomatit Servikal LAP Farenjit 1-2 doz 2mg/kg prednisolon: dramatik cevap Siklik nötropeni ekarte Ataklar arasında hasta asemptomatik

PFAPA: Tedavi Prednisone Tonsillektomi Cimetidine Kolşisin? 2mg/kg/g x 1-2 doz Tonsillektomi Cimetidine 150mg/g Kolşisin? There are no universally accepted curative treatments, but, there are several options besides reassurance and symptomatic relief. Prednisone or equivalent steroid at 2mg/kg/day in 1-2 doses terminates the fever, and has even been proposed as a diagnostic criterion, but has also been noted in some series to shorten the duration to the next fever. Tonsillectomy, whether for treatment of recurrent pharyngitis or in trials of PFAPA treatment has been successful at ending PFAPA in 50-90% in studies and case series. Cimetidine, known to have immunomodulatory effects has been noted in the literature to have varying success in treating PFAPA.

PFAPA: Tonsillektomi sonrası düzelme

PFAPA: Prognoz 1/3 1 yılda iyileşiyor 1/3 2-5 yıl devam Uzun süreli sekel yok, gelişim iyi

Siklik nötropeni Nadir Ateş 5-7 gün, 21 günde bir, ANC <200/mm3 Gingivitis Tanı: CBC X2-3/hf, 6 hf süreyle (ANC <500) ve spontan iyileşme KİA Tx: Semptomatik ise, G-CSF

Düzenli Aralıklı Ateş “Relapsing Fever” Borrelia türü spiroketler (burgdorferi dışı) Ateş 1-6 gün, 4-14 gün aralıkla “kriz” (KB,kalp hızı) sonrasında aşırı terleme, ateşin düşmesi, KB  Kriz sırasında tedavi edilmemiş. ateşe bağlı mortalite Tx: penicillin veya tetracycline Borrelia burdorferi causes Lyme Disease Borrelia endemic to N.America? Yes, reported cases include Canada. 18

FMF Sık rastlanan periyodik ateş sendromu Otozomal resesif Yahudi, Ermeni, Kuzey Afrikalı, Türk, Yunan, İtalyan Pyrin proteinini kodlayan MEFV geninde mutasyon Pyrin: IL-1 üretimi regülasyonunda rol alır 1-3 gün süren ateş + Karin ağrısı +serozit, sinovit Persistan inflamasyon: Sekonder Amiloidoz Kolşisin 19

Hiper IgD Sendromu Otozomal resesif Mevalonat kinaz (MVK) geninde mutasyon >2/3’si 1 yaşından önce 3-7 günlük ateş atakları Titreme Servikal LAP Karın ağrısı, bulantı-kusma, başağrısı, Artralji, artit, aftöz stomatit, pleomorfik döküntü Splenomegali 20

Hiper IgD Sendromu Atak aşılama, viral infeksiyon, travma ve stres ile uyarılabilir Çoğu hastada IgD >100 IU/ml, %80’inde yüksek IgA düzeyi Akut faz reaktanları yükselir Tedavi: NSAD, Oral kortikosteroid TNF-alfa inhibitörleri: olgu sunumları Rekombinant human interlökin 1 reseptor antagonisti (anakinra) 21

TRAPS (TNF receptor-1 associated periodic syndrome) Familial Hibernian ateş/ familial periyodik ateş Otozomal dominant, inkomplet penetrans 55 kDa TNFR-1 gen defekti Sütçocukluğu – 40’lı yaşlar arasında başlayabilir İrlandalı (Hibernian) ve İskoç orijinlilerde daha sık Ateş 5 gün - >2 hafta sürer Konjonktivit, periorbital ödem, fokal migratuar miyalji Döküntü karın ağrısı monoartrit 22

TRAPS (Tedavi) Semptomatik: Glukokortikoidler ve NSAID’ler Kronik tedavi: Anti-TNF (Etanercept) Amiloidozu önler? Anti-TNF’e dirençli ise IL-1 ra (anakinra) Kolşisin’e cevap zayıf 23

Kriyopirin ile birlikte periyodik sendromlar Mutant kriyopirine bağlı aşırı IL-1 beta üretimi Ailevi soğuk otoinflamatuar sendrom Muckle-Wells sendromu Intermittent ateş, urtiker, artralji/artrit Progressif sensörinöral işitme kaybı Sekonder amiloidoz ve nöropati Neonatal başlangıçlı multisistem inflamatuar hastalık Anakinra: amiloidozu da önleyebiliyor 24

Periyodik Ateş Sendromları Periyodisite Diğer Sx Kalıtım Etyoloj_______ PFAPA E H H H S. Nötropeni E Gingivitis OD ELA2 AOM, Sinus Apop Kİ FMF H Poliserözit OR MEFV Döküntü Pyrin HIDS E/H Karın Ağr. OR MVK Döküntü MVKase Artrit Isoprenoidler TRAPS H Miyalji OD TNFRSF1A Periorb ödem TNF reseptör

Düzensiz Aralıklı Ateş Fever at irregular intervals presents more of a challenge in terms of the differential diagnosis because it is much lengthier, but I have highlighted boxes on the table to draw your attention to the most common causes of recurrent fevers at irregular intervals. Specifically, repeated viral infections (EBV being most common), and inflammatory conditions. It is also important to note, however, that no diagnosis can be made. The list of possible etiologies is generated from multiple case reports and series on recurrent fevers. Under neoplasms, lymphomas, leukemias, and neuroblastomas have all been noted to cause fevers. John and Gilsdorf 2002 26

Yaklaşım Dikkatli öykü & FM Ateş paternine karar ver (ateş günlüğü) Sabit mi? Rekürran mı? Süre Eşlik eden belirtiler Hematolojik muayene HSM LAP In the approach the child with recurrent fevers, we recognize that most of the time, these previously well children do not need immediate intervention or empirical treatment from us on their behalf. However, we can be very helpful to our colleagues who we refer these patients onto by gathering some of the initial information and investigations before they arrive for further care. As always, with every patient, the approach to the child with recurrent fever begins with a careful history and physical exam. In our case, this is mainly to rule out any obvious localizing symptoms/signs that would point to an immediate cause of the fever. In particular, our colleagues state that the above points are most helpful to our consultants and having the patient keep a fever diary will be immensely helpful to those who we refer onto.

Ne zaman konsültasyon? Pediatric Infectious Diseases: ≥3 rekürran ateş atağı Even before that, when to refer? There is no literature to support when you would start investigations in a patient with truly recurrent fever. Dr. Susan Kuhn from our ID department thinks it would be reasonable to start investigations after 3 episodes given that the likelihood of repeat viral infections decreases as episodes increase. This is reflected in literature on recurrent fever that notes that it is rare for children to have more than two viral infections with no symptoms (localizing symptom) other than fever. 1 time – common, 2 times – unlucky, 3 times – start looking for another diagnosis other than viral infection

Hangi Testler İstenmeli? İnfeksiyonhastalıkları Testler: CBC TİT Kan Cx ESR/CRP EBV serolojisi (IgM/IgG) QIG Duruma göre: AC Gr – solunum belirtileri Gaita incelemesi – ishal İnce/kalın kan yayması –≤1 yıl endemik bölgeye seyahat Dr. Kuhn suggest the above. ESR/CRP should be done both when the patient is febrile and afebrile. ESR/CRP generally remain elevated in diseases requiring specific interventions (occult bacterial infection, Crohn’s Disease, systemic JRA) whereas they decrease in conditions that either do not require intervention (PFAPA, HIDS) or require it primarily for intervention (FMF). Quantitative immunoglobulins as a screen for immune deficiency.

Hangi Testler İstenmeli? Pediatrik GI: Ek olarak: Hepatobiliyer (ALT, GGT, ALP, lipaz) Fe testleri (ferritin, Fe) Albumin (kayıplar/azalmış. üretim) Gaita testleri (antijen) Liver and pancreatic enzymes – IBD can have hepatic and pancreatic involvement Iron studies – IBD can have subtle blood losses or absorption issues Albumin – IBD can cause increased losses or chronic inflammation leading to decreased production Stool studies – remember that infection can also cause inflammatory bowel disease

Hangi Testler İstenmeli? Pediatrik Romatoloji: Doğrudan romatoloji kliniğine gönderilecekse: CBC Kreatinin, Üre ESR/CRP ateşin 1, 5, 10. günleri Ferritin IgD İdrar Rutin+Mikroskopi İdrar Mevalonik Asid Dr. Miettunen would not order anything other than what infectious diseases would order as infection is still the most common cause of recurrent fever. However, if the story is suspicious for a rheumatologic cause, she would have us order the above prior to the patient being seen in the Rheumatology Clinic.

Hangi Testler İstenmeli? Pediatrik Onkoloji: Testler CBC AC grafisi LAP, HSM, SM, karında kitle vs varsa In terms of the oncologic entities that would cause recurrent fever (lymphoma, leukemia, and neuroblastoma), they would be seen with the combination of physical exam (specifically the above findings) and investigations. Children with neuroblastoma will have other symptoms accompanying the fever. Neuroblastoma - spectrum of neuroblastic tumors (including neuroblastomas, ganglioneuroblastomas, and ganglioneuromas) that arise from primitive sympathetic ganglion cells.

Sık Ateşlenen Çocuk: Prognoz Genellikle çok iyi İncelemelerden sonra tanı yoksa Ateş düşmüş Büyüme/gelişme etkilenmemiş Yeni belirti/bulgu olmadıkça başka teste gerek yok If children with recurrent fevers are investigated and no diagnosis is reached, these kids generally have excellent prognosis. Although an observation was made in a retrospective review of 40 children that those with recurrent fevers had higher than expected neurologic sequelae, (ADHD, developmental delay), no relation to the recurrent fevers has been shown. Petit mal seizures developed in one patient with periodic fever, and another had mitochondrial encephalopathy. Four children with periodic fevers have attention-deficit hyperactivity disorder, and two have developmental delays. (n=29) – Miller et al. 1996 J Pediatr 129:419-423.