dr. ghazala rasool senior registrar medical unit-ii

Dr. Ghazala Rasool Senior Registrar Medical Unit-II

Pyrexia of Unknown Origin In 1961 Petersdorf and Beeson defined PUO as: Fever higher than 38.3 C (101 F) on several occasions Persisting without diagnosis for at least 3 weeks At least 1 week's investigation in hospital A new definition which includes the outpatient setting (which reflects current medical practice) is broader, stipulating: 3 outpatient visits or 3 days in the hospital without elucidation of a cause or 1 week of "intelligent and invasive" ambulatory investigation

Pyrexia of Unknown Origin In 75% cases of PUO, cause can be determined with detailed investigations. In rest, cause remains uncertain. Infections and malgnancies account for most PUOs (25-40% of cases each) Autoimmune/ rheumatological disorders account for 10-20% cases.

Adult Onset Stills Disease Adult Stills disease is an inflammatory disorder characterized by: Quotidian (daily) Fever Arthritis Rash It is uncommon, as observed in many published case series. It has been recognized as an important cause of the fever of the unknown origin (FUO).

History It is named after the English physician George Still (in 1896) who first described it in children. Stills disease has become the eponymous term for systemic onset juvenile idiopathic arthritis. In 1971,the term adult onset still disease was used to describe a series of adult patients who: 1. did not fulfill the criteria for rheumatoid arthritis but 2. who had features similar to the children with systemic onset juvenile idiopathic arthritis.

ETIOLOGY Unknown A variety of infectious triggers have been suggested, including: Viral pathogens, Yersinia enterocolitica and Mycoplasma pneumoniae It has also been suggested that genetic factors are important, for example, human leukocyte antigen (HLA)- B17, B18, B35, and DR2.

EPIDEMIOLOGY A retrospective French study estimated the annual incidence of ASD to be 0.16 cases per 100,000 people. In a large multicenter prospective study from tertiary care hospitals in Turkey, Stills disease has been identified as the most common non infectious inflammatory disease causing FUO in about 13.6% of their patients. 1 1. Kucukardali Y, Oncul O, Cavuslu S, Danaci M, Calangu S, Erdem H, Topcu AW, Adibelli Z, Akova M, Karaali EA, Ozel AM, Bolaman Z, Caka B, Cetin B, Coban E, Karabay O, Karakoc C, Karan MA, Korkmaz S, Sahin GO, Pahsa A, Sirmatel F, Solmazgul E, Ozmen N, Tokatli I, Uzun C, Yakupoglu G, Besirbellioglu BA, Gul HC; Fever of Unknown Origin Study Group. The spectrum of diseases causing fever of unknown origin in Turkey: a multicenter study. Int J Infect Dis. 2008 Jan;12(1):71-9. Epub 2007 Jul 12. PubMed PMID: 17629532.

EPIDEMIOLOGY An equal gender distribution. There is a bimodal age distribution, with: one peak between the ages of 15 and 25 and the second between the ages of 36 and 46. However, patients older than age 70 have been reported.

CLASSIFICATION CRITERIA There is no specific test or combination of tests that can be used to establish the diagnosis of ASD. At least seven sets of diagnostic criteria have been proposed. However, the Japanese criteria, often termed the Yamaguchi criteria, have the highest sensitivity in patients with a definite diagnosis of ASD.

YAMAGUSHI CRITERIA Major Criteria Minor Criteria Exclusion Criteria Temperature > 39C (102.2F) for >1 wk Sore throatInfections,especially sepsis Leukocytosis >10,000/mm 3 ( 80% granulocytes) Lymphadenopathy and/orEpstein-Barr infection Typical RashSplenomegaly or hepatomegaly Malignancy Arthalgias > 2wksAbnormal liver function studies, particularly elevations in AST ALT LDH Inflammatory diseases Negative tests for ANA and rheumatoid factor

AOSD should be considered if 5 criteria (2 of which being major) are met. Once malignancies, infectious diseases and rheumatological diseases have been excluded. The Yamaguchi criteria have a sensitivity of 96% and specificity of 92%.

CLINICAL FEATURES FEVER Daily fever It is usually quotidian or double-quotidian (two fever spikes per day). The temperature swings can be dramatic, with changes of 4C occurring within four hours. Complete defervescence is not required with these fevers, as fever persists between spikes in approximately 20 percent of cases.

RASH The classic rash is Evanescent Salmon-colored Macular or maculopapular eruption Transient that tends to occur with the fever. Predominantly involves trunk and extremities (rarely involve the palms, the soles and face). The Koebner phenomenon may be present, in which the cutaneous eruption can sometimes be elicited by stroking the skin. The rash is frequently misdiagnosed as a drug reaction.

Evanescent rash

MUSCULOSKELETAL Arthralgia, arthritis, and myalgia are universal features. Initially, the arthritis may be mild, transient, and oligoarticular. However may evolve later into a more severe and destructive polyarthritis Fusion of the wrist joints is characteristic. The most commonly involved joints, in descending order are: Knees Wrists Ankles Elbows Proximal interphalangeal joints and shoulders

Clinical Features Pharyngitis Sore throat was noted in 69 % percent. Lymphadenopathy Slightly tender, enlarged cervical lymph nodes (one-half of patients). Splenomegaly / hepatomegaly Pleuropericardial effusions, transient pulmonary infiltrates in 30 to 40 percent of patients. Myocarditis is a rare complication Hematologic manifestations: pure red cell aplasia, DIC, microangiopathic hemolytic anemia including, Reactive hemophagocytic syndrome.

The Disease Complications It can include diverse complications, affecting multiple organ systems. Moreover, the severity of the organ involvement can vary considerably. The clinician should be alerted to the existence of life- threatening AOSD complications, namely: The macrophage activation syndrome. Disseminated intravascular coagulopathy, thrombotic thrombocytopenic purpura, Diffuse alveolar hemorrhage, and pulmonary arterial hypertension. Fulminat hepatic failure.

REACTIVE HEMOPHAGOCYTIC SYNDROME It is termed as macrophage activation syndrome when it occurs in AOSD. Rare but fatal complication, may be underdiagnosed. A retrospective study reported RHS in six (12 percent) out of 50 AOSD patients.

REACTIVE HEMOPHAGOCYTIC SYNDROME Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory condition caused by a highly stimulated but ineffective immune system response. There is uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction

The diagnostic hallmark of RHS is the presence on bone marrow examination of numerous, well-differentiated macrophages (histiocytes) that are engaged actively in the phagocytosis of hematopoietic elements

The Clinical Presentation of Macrophage Activation Syndrome (MAS) Is generally acute and occasionally dramatic. Typically, patients become: acutely ill with the sudden onset of non remitting high fever, profound depression in all 3 blood cell lines, and elevated serum liver enzyme levels, development of DIC.

Other Conditions associated with HLH HLH may also occur as a secondary disorder in association with: severe infections, malignancies, rheumatologic disorders, and some metabolic diseases. This rare phenomenon was first ever diagnosed and reported in our setup by our Dengue team in HFH, caused by Dengue co infection with Malaria.

DISEASE COURSE Monophasic pattern Lasts only weeks to months, completely resolving within less than a year. Intermittent pattern one or more disease flares, with complete remissions between episodes lasting from weeks up to one or two years. Subsequent flares tend to be less severe and of shorter duration. Chronic pattern Persistently active disease, in which articular symptoms usually predominate. A potentially destructive arthritis may occur in patients in this group.

INVESTIGATIONS No specific test or combination of tests that can be used to establish the diagnosis of ASD. Raised ESR an CRP are seen in virtually all patients Normocytic normochromic anemia is seen in the majority of patients. Elevated ALT, AST, LDH are seen in 75 percent of patients. Increased serum ferittin, exceeding 3000 ng/mL, is seen in 70 percent of patients

INVESTIGATIONS (continued) Immunologic studies the absence of antinuclear antibodies and rheumatoid factor is one of the minor criteria for ASD. Bone marrow examination may reveal hyperplasia of granulocytic precursors. Radiographic findings nonerosive narrowing of the carpometacarpal and intercarpal joint spaces of the wrists often progresses to bony ankylosis (40%).

Serum Ferritin Markedly elevated serum ferritin concentrations in as much as 70 percent of patients. More likely to be a consequence of cytokine-induced synthesis by reticulo-endothelial system or of hepatocyte damage with increased release. Hyperferritinaemia is reported by some studies to be associated with hisctiocyets hyperactivity The elevations correlate with disease activity. A serologic marker to monitor the response to treatment.

Glycosylated Ferritin Tends to be lower than in other rheumatic disease. It may remain low both in the active phase of disease and in remission. Both marked hyperferritinemia and a low fraction of glycosylated serum ferritin also occur in the macrophage activation syndrome Both the total serum ferritin and the glycosylated fraction provide more diagnostic specificity for ASD than does reliance upon either test alone.

Predictors of Chronic Disease and Unfavorable Outcome 1. The development of a polyarthritis early in the course of ASD. 2. Involvement of the shoulders or hips. 3. The need for more than two years of systemic glucocorticoid therapy. Functional outcomes The functional status of patients with ASD is generally good, even in the setting of a chronic disease pattern.

TREATMENT Therapeutic decisions should be based upon the extent and severity of organ system involvement. The principal options for treatment are: NSAIDs Glucocorticoids Biologic agents DMARDs

NSAIDS Initial therapy with NSAIDs in patients with relatively mild disease.

GLUCOCORTICOIDS If there is no response to several days of starting NSAID. Patients with debilitating joint symptoms, or internal organ involvement should be started on glucocorticoids from the outset of therapy. Pulse glucocorticoids may be employed initially in patients with life-threatening manifestations such as: severe hepatic involvement, cardiac tamponade, disseminated intravascular coagulation HPS

3BIOLOGICAL AGENTS No response to NSAIDs and glucocorticoids within two to four weeks. a)ANAKINRA (recombinant human interleukin-1 receptor antagonist b)RITUXIMAB (monoclonal antibody ) c) TUMOR NECROSIS FACTOR (TNF) inhibitors Experience with TNF inhibitors remains limited to case reports Promising results have been reported with etanercept, infliximab and adalimumab 4.DMARDS when patients have either not responded sufficiently to NSAIDs, glucocorticoids, or biologic agents METHOTRAXATE (Its most common role is as a glucocorticoid- sparing agent) CYCLOSPORIN

Adult Onset Stills Disease in Pakistan A number of studies and cases have been published internationally and also in Pakistan. A retrospective study was conducted at Agha Khan Hospital Karachi (1995-2005) to study the clinical characteristics of Stills disease in a tertiary care hospital of Pakistan and compare it with similar internationally published studies. 2 2. Abid N, Khalid AB. Adult onset Stills disease in a tertiary care hospital of Pakistan. J Pak Med Assoc. 2009 Jul;59(7):464-7. PubMed PMID: 19579736.

Results 13 patients with ASOD were identified. Fever (100%) Arthralgia, myalgia (100%) Sore throat (53.8%) None of these patients had rash with fever. Lab patterns were also studied which were consistent with international data.

Conclusion Clinical characteristics of Stills disease in our country are mostly similar to those seen in other regions.

Atypical Presentations of Stills Disease Worldwide Different cases of atypical presentations of Stills disease have been reported worldwide, of which two are worth mentioning. Interestingly a case of Fulminant hepatic failure in a patient with newly diagnosed Stills disease has been recently reported. 3 3. Nalini Valluru, Venkata S. Tammana, Michael Windham, Eyasu Mekonen, Rehana Begum, and Andrew Sanderson, Rare Manifestation of a Rare Disease, Acute Liver Failure in Adult Onset Stills Disease: Dramatic Response to Methylprednisolone Pulse TherapyA Case Report and Review, Case Reports in Medicine, vol. 2014, Article ID 375035, 5 pages, 2014. doi:10.1155/2014/375035

A case of an eosinophilic pleural effusion as a novel and unrecognized manifestation of active Stills disease was reported in Greece in 2002. 4 4. Katerina M. Antoniou, George A. Margaritopoulos, Ioannis Giannarakis, et al., Adult Onset Stills Disease: A Case Report with a Rare Clinical Manifestation and Pathophysiological Correlations, Case Reports in Medicine, vol. 2013, Article ID 981232, 4 pages, 2013. doi:10.1155/2013/981232

Case Report A 39-year-old woman was admitted because of a non itching macular-papular rash. In addition, the patient complained of arthralgias, myalgias, fever of 38 degrees C, and night sweats. On admission, a neutrophilic leukocytosis (23.6), An increase in C-reactive protein (185 mg/l), Ferritin level of 1,740 microg/l Liver enzymes were raised. Normal radiological and echocardiographic findings. Repeated blood cultures were negative. Antibiotic therapy was continued without any improvement.

In addition, acetaminophen and ibuprofen were given. Liver function worsened and an icterus developed. A working diagnosis of Still's disease was made. The patient was treated with high-dose methylprednisone (250 mg/day for 3 days, then 100 mg/day). Liver biopsy revealed subacute hepatitis with necrosis and accompanying cholangitis. The prednisone therapy induced a fast remission and improvement of liver function, liver transplantation was not necessary. The patient is, 16 months after the incident, without symptoms under prednisone 3 mg/day, and the liver function is normal.

Conclusion Still's disease must be considered as part of the differential diagnosis of acute liver failure, because an early diagnosis and consequent therapy with prednisone may prevent the need for liver transplantation.

Stills Disease: A Case Report with a Rare Clinical Manifestation Pleuritis is the most common pulmonary manifestation, and pleural effusions are usually exudative with a predominance of neutrophils. A case of an eosinophilic pleural effusion as a novel and unrecognized manifestation of active Stills disease was reported in Greece in 2002.

A 51-year-old woman with a 15 days history of: Chest pain on the left hemithorax, shortness of breath, evening fever (38.5C), and diffuse arthralgias. On admission she was febrile (39.2C) and tachypneic. On physical examination there were findings of left sided pleural effusion. Laboratory findings included WBC count = 12000 cells, (ESR) = 33 mm/h. Chest radiography revealed left sided pleural effusion. Empiric treatment with broad spectrum antibiotics was commenced immediately.

Thoracocentesis revealed an eosinophilic pleural effusion (EPE) (WBC = 5000, neutrophils = 38%, lymphocytes = 30%, and eosinophils = 20%). A work up for diagnosis of EPE was undertaken. Blood, urine, and sputum cultures, stains and cultures of bronchial wash obtained and tuberculin skin testing were all negative for infectious causes. CT scan of chest and abdomen, ultrasound of abdomen, mammography, and FOB ruled out the presence of malignancy. CT pulmonary angiography was negative for pulmonary embolism but revealed a mild right pleural effusion as well

Rheumatoid factor, antinuclear antibodies, were negative. On the fifth day of admission the patient became febrile again (39.4C). There was no evidence suggestive for a connective tissue disease.

The most plausible diagnosis based on clinical and laboratory findings and exclusion of other possible causes of EPE was AOSD (total 4 Yamaguchis criteria, 3 major). The patient was treated with corticosteroids. She was discharged afebrile. Reevaluation after 3 and 6 months showed marked improvement of the radiological and clinical findings.

Take Home Message! In addition to common causes of PUO, there are some uncommon causes as well and Adult onset stills disease is an example in this regard.

dr. ghazala rasool senior registrar medical unit-ii

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