History. Physical Exam. Potpourri of (Peds) ID. Peggy Weintrub, M.D. May 13, 2010
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1 Potpourri of (Peds) ID Peggy Weintrub, M.D. May 13, 2010 History 10 year old boy seen in 4/2010 for bone pain, began in left arm & left foot in 10/09 Initially treated for injury with immobilization but pain worsened No systemic symptoms Started on Indocin 25 mg tid with some improvement in foot, excellent response in arm Bone scan showed lesion in L ulna, L foot at base of 1st metatarsal, 5th metatarsal, calcaneus, cuboid, talus Physical Exam 10 year old male, pleasant and interactive VS: all normal and no abnormalities on PE except: pectus excavatum pain over left calcaneous, no swelling, erythema left ulna larger diameter than right, especially near the wrist. No pain, erythema, swelling 1
2 LABS WBC 6,800 NL differential Hct 37, plt 330K ESR 16, 6 CRP <0.5, 2.2 (nl) B27 antigen: neg Prometheus Panel: neg PPD: 0 mm Cocci serologies: neg Bone Scan 1. Osteomyelitis 2. Still s Disease 3. CRMO 4. IBD What s His DX? 2
3 Chronic Recurrent Multifocal Osteomyelitis Unknown Etiology Presumed auto-immune Often family history of other autoimmune dx Dx of Exclusion Features Seen primarily in young adults, teens and children, cases reported up to 50s Similar to/same spectrum as SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) in adults Female predominance Usually recurrent, relapsing course of multiple sites of sterile osseous inflammation +/- Other concomitant inflammatory condition Associated with multiple skin conditions: pustulosis, psoriasis, Sweet syndrome, PG Susceptiblity locus identified at 18q Features 3
4 Bone Distribution Often bilateral, symmetrical Series of 25 cases at presentation Lower extremities 39.7% Spine 25.9% Pelvis 20.9% Additional (unusual) sites Mandible Clavicle (medial) Scapula Sternum Radiographic Series Study 1 7 children with 14 symptomatic sites Imaging found 20 additional sites Study 2 14 patients 12 had unifocal presentation Bone scan found an average of 6 lesions/patient Radiographic Findings Early- osteolytic lesion in distal metaphysis, similar to bacterial, hematogenous osteo Later-lytic, sclerotic, progressive hyperostosis 4
5 Therapy-Outcome NSAID Steroids Immune modulators Biphosphonates History 6 year old male admitted after 10 days of neck swelling, and fever 5 days PTA, sore throat, abd pain, drooling, cough Rapid strep + and rx with amox Started having hallucinations Admitted OSH and scanned evaluating for abscess (retropharyngeal, peritonsillar) History WBC 11.9, 6.3 Lymph with many large lymphs, Hb 10, plt 99K AST 130, ALT 40, Alb 2.7, LDH 932 Ferritin 8K, Monospot + LP: 1WBC, glu 64, pro 16 nl OP MRI: scattered non-specific foci of T2 prolongation in subcortical white matter (consistent with p/inflammatory, ADEM, migraine or vasculitis) 5
6 Which Test Lead To Dx? 1. HSV PCR of CSF 2. EBV PCR of CSF 3. Tox screen of Urine 4. Lead level-serum Pt s Labs EBV PCR CSF ++++ EBV Serologies VCA IgM + VCA IgG + EBNA - EBV Complications Splenic Rupture Estimated 0.1 to 0.2 % Hematologic: Thrombocyptopenia, Hemolytic Anemia, Neutropenia Pneumonitis Cardiac: Pericarditis, Myocarditis Hepatitis (subclinical 70-79%) Renal: Nephrosis, Nephritis 6
7 Neurologic Complications Estimated 1% of IM patients Commonly seen in absence of IM Most common Cranial nerve palsies Transverse Myelitis, Guillain-Barré Encephalitis 85% with complete recovery Alice in Wonderland metamorphopsia Metamorphopsia The Monospot Less than 4 y.o., sensitivity <20% Older patients usually positive in 2-3 weeks Often negative at initial presentation May persist for up to 9 months 7
8 Monospot Positivity by Age Percent < View of EBV Serologies EBV Serologies 8
9 EBV Diagnosis: Serology IgM-VCA IgG-VCA Ea EBNA Acute 1º + + +/- - Convalescent +/- + +/- + Past Reactivated +/- + +/- + EBV Serologies Primary Infection 101 IgM-VCA + EBNA Conversion within 2-3 weeks History Pt seen at OSH on thur/fri 5 year old girl with 3 weeks of fever without source Daily T, no pattern, no localizing symptoms Temporary response to anti-pyretics No one else ill at home, no ill contacts No travel, unusual exposures 9
10 History/Physical PE remarkable only for T 39, irritable but consolable. Bilat knees, ankles, elbows, all slightly warm, slightly swollen Neck supple No rash, nl chest, abd, nodes, neuro exam Recommended transfer to UCSF to see rheumatology Nl CBC with platelet Bld culture neg X1 ANA, RF neg Labs EBV titers neg CXR, U/A, ur cx neg History Pt transferred on Monday Upon transfer, during first exam, pupils noted to be asymmetric Emergency CT showed enlarged ventricles Straight to OR for EVD Fluid gm stain showed gram negative diplococci- an aha moment! 10
11 What is her Immune Problem? 1. Hypogammaglobulinemia 2. Asplenia 3. Terminal Complement Deficiency 4. Severe Combined Immunodeficiency Complement Complement Cascade 11
12 Complement Deficiencies Early defects- more autoimmune disease Later defects- more infectious disease Terminal components Only Neisseria species Often more mild disease Chronic meningococcemia** Alternative Pathway Often X-linked- Properdin Usually severe, overwhelming infection Chronic Meningococcemia Seen primarily in pts with terminal complement defects Has later onset curve than usual cases Has different serotypes Has prolonged, non-acute course Often requires multiple blood culture for dx On differential for FUO Chronic Menigococcemia Many manifestations related to immune complex disease: Fever Leukocytoclastic vasculitis/rash Arthralgia/arthritis Meningitis 12
13 Characteristics of Patients Parameter NLs TCDs Median age, first episode 3 17 Recurrence Rate (%) Relapse Rate (%) Mortality Serotype B Serotype Y Who To Evaluate- Everyone? 2 Studies Sporadic Meningococcemia 20 Patients with first episode 6/20 had CH50 below 2 SD, 3 congenital, 3 consumption (SLE, MM) All Children 2/11 (18%) with twins counting as one Do Not Test During Hospitalization PIDJ Vol 16, p75. NEJM V308: Complement Evaluation CH50 Tests entire classical pathway C deficient patients have absent, not decreased values C3,C4 usually available C1,2,5-9 Send out individual components Alternative pathway- research labs 13
14 History #1 10 year old male with type I DM and 11 days of fever, malaise, emesis X5 No other PMHx ID questions : travel to Europe 9 mo prior, pet frog, no ill contacts Day of admission- right groin/hip pain MRI: Effusion in right hip, no osteo ESR >100, WBC 8.7, 6P, Jt tap: 46K WBC History #2 Almost 3 year old female with recent gastroenteritis Returned few days after with low grade fever, pain on urination No travel, no ill contacts, no PMhx, pet turtle What Organism do they Have? 1. Group A strep 2. MRSA 3. Salmonella 4. Adenovirus 14
15 Salmonella and Cold Blooded Pets Salmonella Epidemiology-US Estimated 1.4 million infections 74,000 reptile or amphibian associated 15,000 hospitalizations 400 deaths Recent Outbreak- S. typhimurium 85 cases in 31 states by end of 2009 Known outcome n=16/47 (34%) hospitalized MA ---> CA Same PFGE pattern 79% of patients were <10 years old Clear association with African dwarf frog Knew of association with reptiles-53% Knew re: amphibians-31% Most cleaned in kitchen or bathroom sinks 15
16 CDC Recommendations No reptiles or amphibians in home of those who are <5 and/or immunocompromised, none in day care settings Hand Hygiene No free range reptiles/amphibians Clean areas exposed to aquariums By law- no turtles <4 inches sold in US Outbreaks Associated with reptiles and amphibians Animals-high carriage rate but asymptomatic Persistent organisms in the environment Animals shed intermittently, so testing not useful Childhood hand hygiene suboptimal Lack of awareness of association Diabetes and Infection Increase in bacteremia and sepsis UTI, 2/2 neuropathy and bladder residual Increase in SSTI (ulcers, osteo) External Otitis Skull based osteo/sinus infection Mucormycosis Pseudomonas 16
17 History 9 yo boy with episodic fevers + sore throat x 2 years No other associated symptoms No sick contacts/friends/exposures Fevers q 4 weeks and last for less than 5 days Pharyngitis: mono x 1; GAS x 1; culture-negative x2; no other cultures obtained No aphthous ulcers with these episodes, but has had at last three aphthous ulcers in the last year Unclear whether has had adenopathy Well between episodes History No travel history out of country No camping, pets Fam Hx: non-contributory, mixed European descent No ill contacts No well water, un-pasteurized dairy ROS: neg Dx? 1. Borrelia hermsii/ aka tick borne relapsing fever 2. Lymphoma 3. Familial Mediterranean Fever 4. PFAPA 5. How the h!@e_@#$ would I know! 17
18 Periodic Fever Syndromes PFAPA Cyclic Neutropenia FMF (Familial Mediterranean Fever) IyperIgD Syndrome FHF (Familial Hibernian Fever), TRAPS (TNF Receptor Associated Periodic Fever Syndrome) See appendix for chart with distinguishing features Periodic Fever, Apthous Stomatitis, Pharyngitis, Adenitis Inclusion 3 or more episodes of fever of < 5 days at intervals of 3-6 weeks Tender cervical adenopathy, pharyngitis or aphthous ulcers Normal between episodes Exclusion Neutropenia, Fam Hx, Increase ESR, CRP when well Periodic Fever, Apthous Stomatitis, Pharyngitis, Adenitis Sporadic cases No known gene or ethnic predilection Usual onset 2-5 Most resolve within 5-7 years 18
19 Classic Features Sudden onset, often clock like regularity Parents can recognize attacks Poorly responsive to antipyretics Occasional symptoms beyond dx features: Headache, n/v/d, cough, myalgia Treatment Options Cimetidine Steroids Tonsillectomy Response to Agents Data from PFAPA Registry Total NOT Some Moderate Very Acetaminophen (55) 21 (26) 10 (13) 5 (6) Ibuprofen (15) 21 (31) 14 (21) 22 (33) Antibiotics (92) 4 (6) 0 (0) 2 (3) Prednisone 49 5 (10) 2 (4) 5 (10) 37 (76) Cimetidine (57) 1 (4) 3 (11) 8 (29) Tonsillectomy 4 1 (25) 0 (0) 1 (25) 2 (50) T & A 47 1 (14) 1 (14) 0 (0) 5 (72) Adenoidectomy 3 3 (100) 0 (0) 0 (0) 0 (0) 19
20 Cimetidine?? Other small studies 3/3 efficacy- but disease has variable time course Risks of cimetidine: studies of pts with GERD Increase AGE, increase PNA Steroids Not an option for chronic use Abort episodes when used at beginning Excellent for trips and birthdays Variable results on long term course Fewer episodes More frequent episodes Tonsillectomy? Results: 26/27 patients had complete resolution the one child who continued to have febrile episodes had fever cycles that were not regular in duration or interval and in hindsight was not likely a patient with PFAPA syndrome Licamelli et al Arch Oto
21 RCT of children with PFAPA N = 26 Inclusion: At least 5 PFAPA episodes Periodic fever with regular pattern q2-5 weeks Associated with: 29%: Exudative tonsillitis at least once 21%: Cervical LAD, aphthous stomatitis, or mouth/throat pain 41%: No associated symptoms Average 9 febrile episodes (range 4-20) before enrollment Renko, et al. RCT of tonsillectomy in PFAPA. J Peds, 2007 Results Symptoms at 6 mo after randomization: 14/14 tonsillectomy pts symptom-free 6/14 control pts symptom-free p < % difference (95% CI 23-75%, p < 0.001) Fever episodes during 6 mo f/u period 4/14 tonsillectomy pts had 1 fever episode c/w periodic fever Collectively 34 episodes in 12 children in control pts 0.05 vs episodes per person-month at risk 95% CI , p = After the study 5/12 control pts underwent tonsillectomy 5/5 had complete resolution 21
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