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This thesis reviews the current literature on idiopathic pulmonary fibrosis (IPF), a progressive, scarring lung condition largely affecting older adults that is experiencing an increasing incidence in the U.S. and abroad. Two troubling clinical aspects of IPF are the difficulty of timely diagnosis and uncertain progression once diagnosed. The need for early detection is driven by the condition’s median survival rate post-diagnosis of about 3 years. Environmental and familial risk factors are important predictors of IPF, but cannot alone determine who is at risk for the condition. High-resolution computed tomography is currently the best non-invasive diagnostic tool, but many efforts are now underway to identify biological markers, which may aid not only in diagnosis, but illuminate both susceptibility and progression of the disease. Although the pathogenesis of IPF remains unclear, a compelling correlation has surfaced between the mechanics of IPF and herpes virus infection, which also may lead to a biological marker for the condition. Likewise, some genetic factors have shown promise in revealing pathogenesis and possible diagnosis. The only treatment currently available to ameliorate IPF is lung transplantation, but it is a last resort effort. In terms of pharmaceutical treatment, the most significant development has been the recent approval and use of two anti-fibrotic drugs, pirfenidone and nintedanib, that appear to slow the progression of the disease, but do not eliminate the fibrotic condition that impairs patients’ breathing. As efforts progress in addressing affirmative treatments for IPF, there is consensus that not enough is being done to address palliative and psychological needs of IPF. In sum, a review of the current literature suggests tremendous accomplishments have made in treating what remains a fatal condition, but much work remains to truly understand how and why IPF occurs, and whether, short of lung transplantation, there are treatments that can improve, not just maintain, patients’ health.

Aims: To determine the test-retest reliability and responsiveness of a new computerized 20-item pain measure, SUPER-KIDZ, in children with juvenile idiopathic arthritis (JIA). Methods: A single centre prospective cohort study of JIA patients aged 8-18 years was performed. For each SUPER-KIDZ item, test-retest reliability analysis was done in patients expected to have stable pain, and responsiveness was evaluated after intra-articular steroid injection(s). Results: Fifty-one subjects were included. Good internal consistency (α=0.73-0.92) was demonstrated for the 3 SUPER-KIDZ domains. Acceptable test-retest reliability (intraclass correlation coefficient or kappa ≥0.80) was found for 15 SUPER-KIDZ items. At 2 weeks post-injection, 16 items were responsive to change in pain (standardized response mean=0.66-0.82, significant Wilcoxon signed rank and linear mixed model). Conclusions: The majority of the SUPER-KIDZ items have acceptable test-retest reliability and responsiveness properties. If validity is demonstrated, this measure could be implemented as a standardized comprehensive pain tool for JIA patients.

Aims: To determine the test-retest reliability and responsiveness of a new computerized 20-item pain measure, SUPER-KIDZ, in children with juvenile idiopathic arthritis (JIA). Methods: A single centre prospective cohort study of JIA patients aged 8-18 years was performed. For each SUPER-KIDZ item, test-retest reliability analysis was done in patients expected to have stable pain, and responsiveness was evaluated after intra-articular steroid injection(s). Results: Fifty-one subjects were included. Good internal consistency (α=0.73-0.92) was demonstrated for the 3 SUPER-KIDZ domains. Acceptable test-retest reliability (intraclass correlation coefficient or kappa ≥0.80) was found for 15 SUPER-KIDZ items. At 2 weeks post-injection, 16 items were responsive to change in pain (standardized response mean=0.66-0.82, significant Wilcoxon signed rank and linear mixed model). Conclusions: The majority of the SUPER-KIDZ items have acceptable test-retest reliability and responsiveness properties. If validity is demonstrated, this measure could be implemented as a standardized comprehensive pain tool for JIA patients.

A Research Report submitted to the Faculty of Health Sciences, University of Witwatersrand, Johannesburg, in partial fulfilment of the degree of Master of Medicine in the branch of Internal Medicine. / Background. Primary immune thrombocytopenia (ITP) is a rare disease causing significant morbidity. South Africa has a high prevalence of HIV infection which may be associated with immune thrombocytopenia. There is a paucity of clinical, management and outcome data on immune thrombocytopenia in the local South African setting. Objectives. To compare the demographics, clinical presentation, management and treatment outcomes of immune thrombocytopenia in HIV positive and HIV negative patients and to compare the treatment outcomes with established international guidelines. Methods. This was a retrospective comparative study conducted at Charlotte Maxeke Academic Hospital, Johannesburg, from January 2003 to December 2014. Adults (≥ 18 years) with confirmed diagnosis of ITP were included. Hospital charts of eligible patients were reviewed to extract data on their clinical presentation, diagnosis, HIV status, treatment and outcomes. A comparison was made between HIV positive and negative patients. Descriptive analysis was performed on the data and results were presented graphically. The P-value of <0.05 was regarded as significant. Results. A total of 250 patients were screened, of which 154 patients met eligibility criteria for the study. 91% of the patients were female, 58% were HIV negative and 42% were HIV positive. The 25-35 year age-group comprised the highest percentage of HIV positive patients (42%). There was no difference in the presentation of symptoms between HIV positive and HIV negative patients. Response to first line therapy was not significantly different between the HIV positive and HIV negative patients (p=0.1370). The patients who went on second line therapy, showed excellent response with approximately 80% reaching complete response. There was no difference in HIV positive and HIV negative groups. Conclusion. In a large central hospital in a high HIV prevalence setting, there is no significant difference between HIV positive and HIV negative patients in terms of clinical presentation, treatment and outcomes in confirmed patients with immune thrombocytopenia. The management of ITP at the CMJAH is comparable to that of published guidelines. / MT2017

We report a case of a 45-year-old male who presented with a headache, fever, vomiting, somnolence, and difficulty walking for 10 days. His cerebrospinal fluid studies revealed cryptococcal meningitis. Chest and abdominal computed tomography (CT) scans showed splenomegaly along with mediastinal, retroperitoneal and inguinal lymphadenopathy. CD4 count turned out to be 208 μL. Human immunodeficiency virus (HIV) testing, serum protein electrophoresis, serum light chains and quantitative immunoglobulins were non-diagnostic and CD4 lymphopenia was attributed to acute infection. However, a persistent CD4 lymphopenia was seen in subsequent outpatient testing, which prompted a detailed workup for secondary causes of immunodeficiency. Repeated lymph node biopsies with analytic cytometric immunophenotypic analysis were normal, as was the bone marrow biopsy with detailed immunophenotypic and cytogenetic studies. The patient was hence being treated as a case of idiopathic CD4 lymphocytopenia.

IPF is a progressive disease, characterized by dysregulated fibrosis of the extracellular matrix (ECM). The pathobiology of the disease is still unknown, and the median survival post-diagnosis is about 3-5 years. The two current US FDA approved drugs for IPF (nintedanib and pirfenidone) slow, but fail to reverse, disease progression. There is cumulating research that suggests the ECM is an active player in fibrosis. In this thesis, we summarized the current knowledge of ECM-cell interactions in the context of pulmonary fibrosis. To gain more mechanistic insight into the ECM characteristics that dictate cell behavior, we established a 3D ECM ex vivo system to assess the nonfibrotic and fibrotic ECM’s effect on fibroblasts. The ECM appears to promote both pathological and physiological cellular changes, depending on its structural and compositional properties. We also used this 3D ex vivo system as a preclinical tool to test the effect of directly inhibiting mechanotransduction in the fibrotic ECM – fibroblast profibrotic relationship. Lastly, since the fibrotic ECM seems to play a key role in progressive fibrosis, we evaluate if researchers are appropriately using the bleomycin model by starting interventions after ECM fibrosis is established. Over the past decade in the field, there has been an overall improvement in the appropriate therapeutic timing. In the preventative studies, however, there is still an inadequate characterization of inflammation. There is also poor transparency of preclinical-bleomycin data for clinically tested interventions for IPF. Addressing these shortcomings may improve the utility of the model at predicting an intervention’s success in clinical trials. These findings illustrate the ECM’s role in driving pulmonary fibrosis. Therefore, the ECM should be further investigated to understand disease progression, and reproduced in preclinical models to test interventions. This will improve the transition of pathobiological findings into efficient drug development for this devastating disease. / Thesis / Candidate in Philosophy / Idiopathic pulmonary fibrosis (IPF) (idiopathic - unknown cause; pulmonary - lungs; fibrosis - scarring) is characterized by progressive scarring of the lung extracellular matrix (ECM). The ECM is an organ’s backbone that provides structural and biochemical support to surrounding cells. Continued ECM scarring can lead to difficulty breathing, cough, and ultimately death. The cause of IPF is unknown, however, studies suggest that the scarred ECM can promote further scarring, and cause disease progression. In this thesis, we summarized the current knowledge of how the ECM interacts with cells. Using a 3D model we see that depending on the ECM’s structure and composition, it can promote both disease and healthy cellular changes. Lastly, we evaluate if researchers are appropriately using the bleomycin model (most common preclinical model for pulmonary fibrosis) by testing interventions after ECM fibrosis is established. We propose changes to improve its usefulness as a preclinical tool for IPF.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

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