Why Is Whipple's Disease Still a Challenging Diagnosis? A Case Report and Brief Review of Literature.

Whipple's disease (WD) is a rare multisystemic infectious disease caused by Tropheryma whipplei. The pathogenesis of Whipple's disease remains unknown and clinical experience relies solely on various case reports published in the literature. The disease may occur at any age, with most studies describing patients in their fifth decade. Classic WD mainly affects the gastrointestinal tract, but extraintestinal commitment can occur, with the most common manifestations being arthralgias, lymphadenopathy, fever, and neurological symptoms. We present a case of a 69-year-old woman who presented with fever, macular rash, abdominal pain, lymphadenopathy, pleural and pericardial effusion, weight loss, and severely altered mental status over seven days. Initial workup tests only revealed leucopenia, thrombocytopenia, and hyperferritinemia. Since the fever persisted despite antibiotic treatment, an extensive workup was required until the final diagnosis of classic WD through histological examination of duodenal biopsies. Treatment with ceftriaxone was implemented for two weeks, followed by trimethoprim-sulfamethoxazole 160/800mg bid for 12 months. The patient presented full recovery and no recurrence after three years of follow-up. Even though WD was first described more than a century ago, WD is an elusive disease with a wide variety of clinical findings, leading to a still significant delay in diagnosis. WD should be considered in the differential diagnosis of rheumatologic disorders, chronic abdominal pain or diarrhea, neurological manifestations not suggestive of any other specific disease, non-caseating granulomatous diseases, and cases of lymphadenopathies. The authors aim to add additional clinical data and raise awareness for a rare condition that can be lethal if not timely treated. More studies and recommendations are needed concerning screening patients and treatment, with an urgent need to improve the delay in diagnosis.

Type 1 Diabetes Mellitus and Multiple Sclerosis: An Association to Consider.

Type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS) have been described as chronic organ-specific diseases, approached by different medical specialties. However, they share more etiologic and pathologic features than expected between two autoimmune diseases. The authors present the case of a 40-year-old Caucasian male, diagnosed with type 1 diabetes mellitus at age 18, with poor metabolic control in the early years after the diagnosis. Fourteen years after the diagnosis of diabetes, he started complaining of paresthesias in both feet and sexual dysfunction. Months later, he began to have episodes of muscle weakness and decreased strength in the right lower limb, with a relapsing-remitting pattern and diplopia. This typical course of the symptoms associated with characteristic findings in brain magnetic resonance imaging, with multiple lesions, with evidence of space and time dissemination, established the diagnosis of multiple sclerosis. The presence of oligoclonal bands in the cerebrospinal fluid analysis sustained this diagnosis. Other alternative etiologies were excluded. People with type 1 diabetes mellitus are at an increased risk for other autoimmune diseases, with autoimmune thyroiditis (AIT), celiac disease, and pernicious anemia being the most common. Other less recognized associations, such as the co-occurrence of type 1 diabetes mellitus and multiple sclerosis, are also more frequent than might be thought, with studies reporting a threefold to fivefold higher prevalence of T1D in patients with MS. The exact mechanism behind this co-occurrence is not fully understood, but environmental factors (viral infections and vitamin D deficiency) and variations in non-human leucocyte antigen (HLA) class II alleles may be implicated. Understanding the similarities in the etiology and pathophysiology of these diseases may help clarify causality and create new strategies for the management of these conditions.

Virus and Autoimmunity: Can SARS-CoV-2 Trigger Large Vessel Vasculitis?

Introduction: Viral infections can induce autoimmune diseases in susceptible patients. SARS-CoV-2 has been associated with the development of rheumatic disease, especially small vessel vasculitis and arthritis. Typically, onset occurs days to weeks after the antigenic challenge and in patients with mild COVID-19. We report a case of large vessel vasculitis (LVV) temporally related to SARS-CoV-2 infection. Case description: An otherwise healthy 19-year-old woman presented with fatigue, malaise, and chest and low back pain. The symptoms had begun 5 weeks earlier and 1 month after mild SARS-CoV-2 infection. Serological work-up revealed a marked proinflammatory state and anaemia without signs of infectious or autoimmune disease. Computerized tomography revealed thickening and blurring of the perivascular fat of the descending thoracic and abdominal aorta, progressing along the proximal iliac and renal arteries. Fluorodeoxyglucose positron emission tomography confirmed inflammatory activity. Symptoms and laboratory values normalized after prednisolone treatment. Discussion: Recent SARS-CoV-2 infection may be a trigger for LVV, including Takayasu arteritis, as well as other rheumatic diseases. A prompt and thorough differential diagnosis is essential to exclude aortitis and LVV mimickers. Moreover, physicians should be aware of the potential spectrum of systemic and autoimmune diseases that could be precipitated by SARS-CoV-2 infection. This will allow timely diagnosis and treatment, with significant improvement in prognosis. LEARNING POINTS: SARS-CoV-2 infection can trigger large vessel vasculitis and other rheumatic diseases.Awareness of the association between COVID-19 and autoimmune phenomena allows for timely diagnosis and treatment with significant improvements in prognosis.Vasculitis and other autoimmune diseases should be kept in mind in patients who develop proinflammatory states days to weeks after an initial antigenic challenge.

Association of Statins With Functional Outcome and 30-Day Mortality in Patients With Intracerebral Hemorrhage.

Aim The effect of statins is well established in cardiac and cerebrovascular diseases. However, its impact on intracerebral hemorrhage (ICH) is unclear. We aim to identify an association of pre-ICH statin treatment and statin use during admission for ICH with functional outcome at discharge and 30-day mortality. Material and methods A retrospective cohort study was held in patients with ICH admitted to our stroke unit over a year period. Demographic characteristics, risk factors and cardiovascular diseases, Glasgow Coma Scale (GCS), National Institutes of Health Stroke Score (NIHSS), systolic blood pressure (SBP) at admission, cholesterol levels and radiologic findings were analyzed to explore the association between pre-ICH and inpatient statin use with outcomes. The primary endpoint was functional outcome defined as modified Rankin Score (mRS) at discharge and 30-day mortality. We performed a univariate analysis and the variables with statistical significance were included in a multivariate analysis to control for confounding covariates. Results The study included 78 patients, 33 (42.31%) had previous statin intake history, of which 13 (39.39%) maintained statin intake during hospitalization. Regarding functional outcome we did not report a statistically significant difference between groups. In the "pre-ICH statin use" group a decreased 30-day mortality (6.06%, p = 0.009) was observed. In this group it was also noted higher antiplatelet medication use (33.33%, p = 0.006), higher GCS at admission (13-15: 84.38%, p = 0.018) and deep ICH (81.82%, p = 0.030). However, 30-day mortality had no impact in multivariate regression (Odds ratio (OR) 4.535, 95% Confidence Interval (CI) = 0.786-26.173, p = 0.091). In the group that maintained statin treatment during hospitalization no deaths were registered (p = 0.020) and there was no association with functional status. Multivariate regression analysis was not performed due to sample size. Conclusion The only association demonstrated in this study was lower 30-day mortality with pre-ICH statin use and continued statin treatment during admission. However, this was not confirmed by multivariate regression analysis. There were no differences between groups concerning cholesterol values, results that can be explained by the pleiotropic and immunomodulatory effect of statins. However, prospective studies are needed to prove the benefit of the statins in ICH.

Intrathoracic Acute Cholecystitis.

The authors present the case of a 51-year-old woman with no history of surgical or traumatic injury or accident, who presented with right hypochondrium and epigastric discomfort, malaise, nausea, loss of appetite and episodes of dark urine and greenish stools. Initial laboratory work-up revealed elevated inflammatory markers including leucocytosis with left shift and C-reactive protein, and a slight elevation of gamma-glutamyltransferase and alkaline phosphatase, with no other significant alterations. Computed tomography (CT) showed intrathoracic acute cholecystitis with a large diaphragmatic hernia. A literature search revealed only one other case of acute cholecystitis complicated by intrathoracic gallbladder due to a non-traumatic diaphragmatic hernia. Symptoms are uncharacteristic and the absence of pain or fever, explained by the altered location of the gallbladder, makes the diagnosis a challenge. LEARNING POINTS: Only one other case of acute cholecystitis complicated by intrathoracic gallbladder due to a non-traumatic diaphragmatic hernia has been reported.Uncharacteristic symptoms make the diagnosis of intrathoracic acute cholecystitis a challenge.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

Churg-Strauss syndrome, Eosinophilic granulomatosis with polyangiitis (EGPA), is a systemic vasculitis that affects small- to medium-sized vessels. It is rare and part of the Anti-neutrophil cytoplasm antibody-associated vasculitis (ANCA) group. We present a 37-year-old man, with a previous history of asthma, that was sent to the ED due to 2 weeks of productive cough, occasional dyspnea on exertion, fever (one week), asthenia, and anorexia. Upon physical examination, he was subfebrile and tachycardic. He had leukocytosis (17.00 x10^9/L) and eosinophilia of 20.0 % (3.4 X10^9/L), creatinine level of 1.5 mg/dL, subtle elevation on liver function tests and CRP of 10.82mg/dL. On Chest X-Ray, there was infiltrate on the right pulmonary base. Due to a strong suspicion of EGPA, he was started on 80mg of prednisolone from admission. ANCA MPO was positive, with the remaining auto-immune study negative. He underwent Thorax CT (under corticotherapy) without relevant changes, as well as bronchoalveolar lavage, without macroscopic signs of alveolar hemorrhage. Because of active urinary sediment, nephrotic proteinuria (6.5g/24h), and acute renal failure he underwent a renal biopsy, which revealed pauci-immune crescentic glomerulonephritis, with predominantly acute findings (in the context of ANCA-MPO Vasculitis - EGPA). After the biopsy, he received three 1g methylprednisolone pulses and was started on Cyclophosphamide. He remained asymptomatic and renal function was restored. This case highlights the importance of integrating all findings in one clinical scenario to prevent a more complex disease diagnosis, with a specific treatment, from being missed.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

SUMMARY Churg-Strauss syndrome, Eosinophilic granulomatosis with polyangiitis (EGPA), is a systemic vasculitis that affects small- to medium-sized vessels. It is rare and part of the Anti-neutrophil cytoplasm antibody-associated vasculitis (ANCA) group. We present a 37-year-old man, with a previous history of asthma, that was sent to the ED due to 2 weeks of productive cough, occasional dyspnea on exertion, fever (one week), asthenia, and anorexia. Upon physical examination, he was subfebrile and tachycardic. He had leukocytosis (17.00 x10^9/L) and eosinophilia of 20.0 % (3.4 X10^9/L), creatinine level of 1.5 mg/dL, subtle elevation on liver function tests and CRP of 10.82mg/dL. On Chest X-Ray, there was infiltrate on the right pulmonary base. Due to a strong suspicion of EGPA, he was started on 80mg of prednisolone from admission. ANCA MPO was positive, with the remaining auto-immune study negative. He underwent Thorax CT (under corticotherapy) without relevant changes, as well as bronchoalveolar lavage, without macroscopic signs of alveolar hemorrhage. Because of active urinary sediment, nephrotic proteinuria (6.5g/24h), and acute renal failure he underwent a renal biopsy, which revealed pauci-immune crescentic glomerulonephritis, with predominantly acute findings (in the context of ANCA-MPO Vasculitis - EGPA). After the biopsy, he received three 1g methylprednisolone pulses and was started on Cyclophosphamide. He remained asymptomatic and renal function was restored. This case highlights the importance of integrating all findings in one clinical scenario to prevent a more complex disease diagnosis, with a specific treatment, from being missed.

RESUMO A vasculite de Churg-Strauss, granulomatose eosinofílica com poliangeíte (EGPA), é uma vasculite sistêmica que afeta vasos de pequeno e médio calibre. É rara e pertence ao grupo de vasculites associadas a anticorpos anticitoplasma de neutrófilos (Anca). Apresenta-se um homem de 37 anos, com antecedentes de asma, que recorre ao SU por tosse produtiva com dois meses de evolução, dispneia ocasional em esforço, febre (uma semana de evolução), astenia e anorexia. Ao exame objetivo apresentava-se subfebril e taquicárdico. Analiticamente com leucocitose (17,00 x10^9/L) e eosinofilia de 20,0% (3,4 X10^9/L), creatinina de 1,5 mg/dL, discreta alteração das provas de função hepática e PCR de 10,82 mg/dL. Na radiografia de tórax objetivava-se infiltrado na base pulmonar direita. Por elevada suspeita de EGPA, iniciou prednisolona 80 mg desde a admissão. Anca MPO+, com restante estudo de autoimunidade negativo. Realizou TC tórax (sob corticoterapia) sem alterações de relevo, bem como lavado bronco-alveolar, sem sinais macroscópicos de hemorragia alveolar. Por sedimento urinário ativo, proteinúria na faixa nefrótica (6,56 g/24h) e lesão renal aguda, realizou biópsia renal que revelou glomerulonefrite crescêntica pauci-imune, com achados predominantemente agudos (no contexto de Vasculite Anca-MPO - EGPA). Após biópsia, realizou três pulsos de 1 g de metilprednisolona e iniciou ainda ciclofosfamida. Ficou assintomático e com recuperação da função renal. Este caso realça a importância de integração de todos os achados num só cenário a fim de evitar que escape o diagnóstico de uma doença mais complexa e com um tratamento específico.

Autoimmune Polyglandular Syndrome type 2

SUMMARY Autoimmune polyglandular syndrome type 2 (APS 2) is defined by the presence of Addison's disease (AD) associated with autoimmune thyroid disease and/or Type 1 diabetes mellitus (T1DM). It is a rare disease, affecting about 1.4-2 cases/100,000 inhabitants. Its less frequent clinical presentation is the combination of AD, Graves' disease, and T1DM. We present the case of a 42-year-old woman with a history of total thyroidectomy due to Graves' disease, type 2 diabetes mellitus, and hypertension, who sought the ED due to asthenia, dizziness, nausea, and vomiting. She reported having stopped antihypertensive therapy due to hypotension and presented a glycemic record with frequent hypoglycemia. On physical examination, she had cutaneous hyperpigmentation. She had no leukocytosis, anemia, hypoglycemia, hyponatremia or hyperkalemia, and a negative PCR. Serum cortisol <0.5 ug/dl (4,3-22,4), urine free cortisol 9 ug/24h (28-214), ACTH 1384 pg/mL (4,7-48,8), aldosterone and renin in erect position of 0 pg/ml (41-323) and 430.7 uUI/ml (4.4-46.1) respectively. Quantiferon TB was negative; computerized axial tomography of the adrenals showed no infiltrations, hemorrhage, or masses. The 21-hydroxylase antibody assay was positive. B12 vitamin was normal, anti-GAD antibodies were positive, anti-insulin, anti-IA2, and anti-transglutaminase antibodies were all negative. The patient started insulin therapy and treatment for AD with prednisolone and fludrocortisone with good clinical response. This case aims to alert to the need for high clinical suspicion in the diagnosis of AD. Since this is a rare autoimmune disease, it is important to screen for other autoimmune diseases in order to exclude APS.

RESUMO A síndrome poliglandular autoimune tipo 2 (SPGA2) é definida pela presença de doença de Addison (DA) associada à doença tiroideia autoimune e/ou diabetes mellitus tipo 1 (DMT1). Trata-se de uma doença rara, afetando cerca de 1,4-2 casos/100.000 habitantes. A apresentação clínica menos frequente é a combinação de DA, doença de Graves e DMT1. Apresenta-se mulher de 42 anos, com antecedentes de tiroidectomia total por doença de Graves, diabetes mellitus tipo 2 e hipertensão, que recorre ao SU por quadro arrastado de astenia, emagrecimento, tonturas, náuseas e vômitos. Referia ter suspendido terapêutica anti-hipertensora por hipotensão e apresentava registro glicêmico com hipoglicemias frequentes. Ao exame físico, salientava hiperpigmentação cutânea. Analiticamente sem leucocitose, anemia, hipoglicemia, hiponatremia ou hipercaliemia, PCR negativa. Cortisol sérico matinal <0,5 ug/dl (4,3-22,4), cortisol livre na urina 9 ug/24h (28-214), ACTH 1.384 pg/mL (4,7-48,8), aldosterona e renina em posição ereta de 0 pg/mL (41-323) e 430,7 uUI/mL (4,4-46,1), respectivamente. Realizado estudo complementar para averiguar causa de insuficiência suprarrenal primária. Quantiferon TB negativo, tomografia axial computadorizada das suprarrenais sem infiltrações, hemorragia ou massas. Anticorpos anti-21-hidroxilase positivos. Foi aprofundada a investigação com vitamina B12 normal, anti-GAD positivo, anti-insulina, anti-IA2, antitransglutaminase, negativos. Nesse contexto, a doente iniciou insulinoterapia e tratamento dirigido para a DA com prednisolona e fludrocortisona, com boa resposta clínica. Este caso tem como objetivo alertar para a necessidade de elevada suspeição clínica no diagnóstico de DA. Sendo esta uma doença autoimune rara, é importante rastrear outras doenças autoimunes no sentido de excluir SPGA.

Autoimmune Polyglandular Syndrome type 2.

Autoimmune polyglandular syndrome type 2 (APS 2) is defined by the presence of Addison's disease (AD) associated with autoimmune thyroid disease and/or Type 1 diabetes mellitus (T1DM). It is a rare disease, affecting about 1.4-2 cases/100,000 inhabitants. Its less frequent clinical presentation is the combination of AD, Graves' disease, and T1DM. We present the case of a 42-year-old woman with a history of total thyroidectomy due to Graves' disease, type 2 diabetes mellitus, and hypertension, who sought the ED due to asthenia, dizziness, nausea, and vomiting. She reported having stopped antihypertensive therapy due to hypotension and presented a glycemic record with frequent hypoglycemia. On physical examination, she had cutaneous hyperpigmentation. She had no leukocytosis, anemia, hypoglycemia, hyponatremia or hyperkalemia, and a negative PCR. Serum cortisol <0.5 ug/dl (4,3-22,4), urine free cortisol 9 ug/24h (28-214), ACTH 1384 pg/mL (4,7-48,8), aldosterone and renin in erect position of 0 pg/ml (41-323) and 430.7 uUI/ml (4.4-46.1) respectively. Quantiferon TB was negative; computerized axial tomography of the adrenals showed no infiltrations, hemorrhage, or masses. The 21-hydroxylase antibody assay was positive. B12 vitamin was normal, anti-GAD antibodies were positive, anti-insulin, anti-IA2, and anti-transglutaminase antibodies were all negative. The patient started insulin therapy and treatment for AD with prednisolone and fludrocortisone with good clinical response. This case aims to alert to the need for high clinical suspicion in the diagnosis of AD. Since this is a rare autoimmune disease, it is important to screen for other autoimmune diseases in order to exclude APS.

Extracorporeal Membrane Oxygenation for Refractory Severe Respiratory Failure in Acute Interstitial Pneumonia.

Acute interstitial pneumonia (AIP) is a rare idiopathic interstitial lung disease with rapid progressive respiratory failure and high mortality. In the present report, three cases of AIP complicated by refractory respiratory failure supported with extracorporeal membrane oxygenation (ECMO) are presented. One male and two female patients (ages 27-59) were included. Venovenous ECMO support was provided using miniaturized systems, with two-site femoro-jugular circuit configuration. Despite lung protective ventilation, prone position and neuromuscular blockade, refractory respiratory failure of unknown etiology supervened (ratio of arterial oxygen partial pressure to fractional inspired oxygen 46-130) and ECMO was initiated after 3-7 days of mechanical ventilation. AIP diagnosis was established after exclusion of infectious and noninfectious acute respiratory distress syndrome on the basis of clinical and analytical data, bronchoalveolar lavage analysis and lung imaging, with a confirmatory surgical lung biopsy revealing diffuse alveolar damage of unknown etiology. Immunosuppressive treatment consisted in high-dose corticosteroids and cyclophosphamide in one case. Two patients survived to hospital discharge. ECMO allowed AIP diagnosis and treatment in the presence of refractory respiratory failure, therefore reducing ventilator-induced lung injury and bridging lung recovery in two patients. ECMO referral should be considered in refractory respiratory failure if AIP is suspected.