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Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality worldwide. In this thesis, different aspects of both management and prognosis of adults admitted with CAP have been addressed in separate parts. In the first part, we evaluated empirical antibiotic therapy and statins as adjunctive therapy. Since the optimal empirical antibiotic strategy for patients with CAP admitted to non-ICU wards was unknown, we have performed a multi-center cluster randomized cross-over trial in 7 Dutch hospitals comparing three empirical antibiotic strategies (CAP-START study). Among 2,283 patients with a working diagnosis of CAP, the absolute risk differences on 90-day mortality were 1.9% (-0.6%; 4.4%) and -0.6% (-2.8%; 1.9%) for beta-lactam/ macrolide combination and fluoroquinolone monotherapy, respectively, as compared to beta-lactam monotherapy, demonstrating non-inferiority of beta-lactam monotherapy by the pre-specified 3% non-inferiority margin. There were no major differences in secondary outcomes or costs. Furthermore, in a post-hoc analysis of this trial, macrolide use was associated with hospital-acquired cardiac complications (HR 1.61, 95% CI 1.14-2.26), which, although we cannot fully exclude observational bias, adds to the changing risk-benefit assessment of macrolides as empirical treatment in this patient population. Given these observations, the lack of superiority, and the threat of increasing antimicrobial resistance, beta-lactam/ macrolide combination therapy and fluoroquinolone monotherapy should not be universally advised as empirical therapy for CAP patients admitted to non-ICU wards. Next, we have evaluated the role of statins as adjunctive therapy in CAP in a systematic review; at this moment, there is a lack of evidence to support this role. In part two, concerning the prognosis of CAP, we have evaluated the prediction of mortality and cardiac complications using data from the CAP-START study cohort. First, we studied the additional value of commonly available ‘biomarkers’ (i.e. the neutrophil/ lymphocyte ratio (NLR) and admission glucose levels) to existing prediction systems. In 1,549 patients with radiologically confirmed CAP, the NLR was associated with mortality, OR 1.19 (95% CI 1.02-1.38) per ten units increase, but did not improve prediction systems with non-significant AUC differences when added to pneumonia-severity-index (PSI) (0.752 vs 0.761, p=0.10) and CURB-65 (confusion, uremia, respiratory rate, blood pressure, age ≥65 years) score (0.698 vs 0.709, p=0.246). Admission glucose level has a significant non-linear association with 30-day, but its addition to models with PSI and CURB-65 score also hardly improved model discrimination (AUC change for PSI: from 0.747 to 0.764, p=0.156 and for CURB-65 score: from 0.697 to 0.722, p=0.082). Next, in the 2,107 patients with a working diagnosis of CAP, admitted without a cardiac event on presentation, the incidence of hospital-acquired cardiac events was 6.9%. The hospital-mortality rate of these patients was 9.6%, and the overall hospital-mortality rate was 3.1%, of which 14.4% (95% CI 6.9-22.0%) was attributable to hospital-acquired cardiac events. Ages, comorbid cardiac disease, diabetes, increasing levels of blood urea nitrogen and C-reactive protein on admission were independent risk factors. Recognition of patients at high risk for these complications, might aid in developing preventive strategies to improve outcome.

Since the introduction of antiretroviral therapy (ART) almost two decades ago, the course of an HIV infection has shifted from acute illness with high mortality towards a chronic disease with good life expectancy. Alongside the improved survival, new comorbidities have emerged as well amongst the group of patients that is living with chronic HIV. Until now, most research on long-term comorbidities in this population has been performed among Western patients in Europe and the United States. Relatively little is known about the long-term effects of HIV in people with African ethnicity, while the majority of the worldwide HIV population resides in Sub-Saharan Africa (SSA). The course of an HIV infection may be different among people of African ethnicity compared with Western populations. This thesis aimed to address some aspects of treating HIV and African origin, both looking at the role of African ethnicity within a Western country such as the Netherlands, and studying some long-term effects of HIV in a rural area in South Africa. In part 1, we looked into the role of genetic diversity by comparing individuals from African origin with people originating from Western European countries within the Dutch HIV population. We made use of the observational AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. We investigated the occurrence of Pneumocystis jirovecii pneumonia (PJP), a frequently diagnosed opportunistic infection among HIV-infected people. Moreover, we studied the role of African ethnicity as a risk for chronic kidney disease (CKD) in HIV in the current treatment era. The results showed that host factors such as genetic variability play a role in the occurrence of opportunistic infections and long-term complications such as CKD. Knowledge on the potential effects of a different genetic makeup in people of African ancestry will contribute to improved HIV care. For the second part of the thesis, treatment of HIV infection and some of its associated long-term complications were studied in SSA. The setting of the research was Elandsdoorn, a township situated in a poor, rural area in Limpopo, a province in the northeast of South Africa. The results of a study looking into the efficacy of second-line ART show that good long-term clinical and virological outcomes following first-line failure can be achieved. On-going evaluation of the efficacy of ART is warranted. In addition, we performed a cross-sectional observational study focusing on renal and cardiovascular disease to have a look into the prevalence of non-communicable diseases (NCDs) in HIV infection. Over 900 patients were screened. Albuminuria and atherosclerotic disease were observed in a substantial proportion of the study population, and were associated with traditional lifestyle-related risk factors. On the other hand, HIV determinants were not related to subclinical atherosclerosis. Prevention and treatment of cardiovascular risk factors are not routinely implemented in the current health service delivery in SSA, while the burden of NCDs is only expected to increase. Continuity care models integrating HIV and NCD care can be a solution. This requires a reorganization of financial resources and is a major challenge for the near future.

In the first part of this thesis we discuss a concise stepwise approach for the diagnostic evaluation of adrenal insufficiency (AI), taking into account the possible pitfalls associated with the different tests. The second part describes the history of replacement therapy, discusses the current imperfections and gives a perspective on future developments. Next, we discuss the results of the use of salivary cortisol day curves in the individual adjustment of therapy in AI, showing that over-replacement and sleep disturbances decreased significantly. We believe that a salivary cortisol day curve is a simple and patient friendly tool and can be useful in the follow-up of patients with AI. We performed a postal survey among patients with Addison’s disease (AD) and studied their ability to be physically active. Sixty-one percent of patients with AD had severe fatigue and we found reduced general subjective health related quality of life scores. We found that patients with AD are less physically active. Next, we assessed the prevalence of abnormal anthropometric and metabolic parameters and the metabolic syndrome in AD. We found that the prevalence of abdominal obesity, hypertension and hypertriglyceridemia was higher in female patients. The metabolic syndrome was not more prevalent. Epidemiological studies on the frequency of infections in AD were lacking. In our cohort study we found that the risk of infectious episodes, defined by the use of antimicrobial agents was 1.5 times higher and the risk of hospital admission as a result of infection was 4.5 times higher in AD as compared to sex and age matched controls. In case of illness or stress patients with AD have to increase their glucocorticoid dose to avoid a life threatening adrenal crisis (AC). We performed a retrospective analysis on the incidence, precipitating causes and risk factors of AC in Dutch patients with AI. We found an incidence rate of 5.2 AC/100 person years in primary, 3.6 AC/100 person years in secondary as compared to 15,1 AC/100 person years in tertiary AI (overall 4.1 AC/ 100 person years). The most important precipitating factor for AC was infection, mostly gastro-enteritis and bronchopulmonary infection. Patients with concomitant pulmonary, cardiac, malignant or neurological disease had a significantly higher risk for AC. We found a patient with primary AI caused by autoimmune adrenalitis in whom partial remission was observed after 7 years of treatment. This prompted us to perform a study aimed at finding more cases of (partial) recovery of adrenal function. More than 60% of participants did not have any response after a standard dosage (250 microgram) of ACTH. Ten patients only showed a slight increase in cortisol. In our study we found no new cases of (partial) adrenocortical recovery. In our opinion, the most plausible explanation for the absent cortisol responses was complete destruction of cortisol producing adrenocortical tissue. We concluded that recovery of adrenocortical function is probably very rare as opposed to the more frequently occurring recovery of Hashimoto’s thyroiditis. Based on our results, we cannot recommend to routinely test Addison’s patients for adrenocortical recovery.

Tuberculosis remains to be one of the severe infectious diseases, especially in developing countries. Universal and specific biomarkers for TB could accelerate the development of novel diagnostics and therapies for TB, which are urgently needed to control the epidemic effectively. In the studies included in this thesis, several candidate biomarkers for latent and active TB have been identified. Our study design for testing novel Mtb antigens, revealed combined measurement of specific cytokines (IFN-γ, TNF-α, IL-6 and IL-10) in response to a subset of antigens (Rv0081, Rv2629, Rv1733c, Rv2006) could be a promising path to develop immunodiagnostics. We also presented data, which suggest combined measurement of IFN-γ IFN F γ-17, and IP-10 in response to ESAT-6/CFP-10 could be useful immune markers for the diagnosis LTBI; IL-2 and IP-10 for the diagnosis of active TB; and IFN-γ, IL-17, MIP-1α, and IL-10 to discriminate latent and active TB. In addition, FCGR1A, TIMP-2, IL-7R and CD8A whole blood genes could be useful to classify active TB in HIV patients We showed that IL-2, IFN-γ and IP-10 in response ESAT-6/CFP-10; and the leukocyte subsets (TLC, WBC, neutrophil) to be useful markers to monitor treatment in HIV negative TB patients. Similarly, IL-10 and MIP-1α in response to ESAT-6/CFP-10 may assist to monitor TB treatment and HAART. In summary, whereas we feel that these identified biomarkers will have significant contribution towards TB control in the future, the effects of other potential confounding factors including endemic infections such as malaria and helminthes, granulomatous disease, host genetics, and Mtb lineages need to be addressed before these new biomarkers are moving to clinical practices. Thus, we propose context-dependent validation studies by comparing findings from prospective cohorts from different epidemiological settings and populations with samples and data collected in a standardised way. The ideal approach for this will be the GC-6-74 TB consortium repository samples which consists of five African countries including Ethiopia, Uganda, South Africa, The Gambia and Malawi. We suggest further biomarker research by including extrapulumonary TB patients and children where the need of better TB diagnostics is enormous; and from other easy to access specimens including urine, saliva and sputum. To increase the efficiency of biomarker discovery and consecutively to deliver novel clinical tests, there is a need of better understanding of the TB biomarker research process (from study design to validation). Nonetheless, research aimed to understand host-pathogen interactions, the interplay between innate and adaptive immune responses, and the complex cytokine interplay need to be continued.