Adult-onset immunodeficiency in Thailand and Taiwan.

BACKGROUND: Autoantibodies against interferon-γ are associated with severe disseminated opportunistic infection, but their importance and prevalence are unknown. METHODS: We enrolled 203 persons from sites in Thailand and Taiwan in five groups: 52 patients with disseminated, rapidly or slowly growing, nontuberculous mycobacterial infection (group 1); 45 patients with another opportunistic infection, with or without nontuberculous mycobacterial infection (group 2); 9 patients with disseminated tuberculosis (group 3); 49 patients with pulmonary tuberculosis (group 4); and 48 healthy controls (group 5). Clinical histories were recorded, and blood specimens were obtained. RESULTS: Patients in groups 1 and 2 had CD4+ T-lymphocyte counts that were similar to those in patients in groups 4 and 5, and they were not infected with the human immunodeficiency virus (HIV). Washed cells obtained from patients in groups 1 and 2 had intact cytokine production and a response to cytokine stimulation. In contrast, plasma obtained from these patients inhibited the activity of interferon-γ in normal cells. High-titer anti-interferon-γ autoantibodies were detected in 81% of patients in group 1, 96% of patients in group 2, 11% of patients in group 3, 2% of patients in group 4, and 2% of controls (group 5). Forty other anticytokine autoantibodies were assayed. One patient with cryptococcal meningitis had autoantibodies only against granulocyte-macrophage colony-stimulating factor. No other anticytokine autoantibodies or genetic defects correlated with infections. There was no familial clustering. CONCLUSIONS: Neutralizing anti-interferon-γ autoantibodies were detected in 88% of Asian adults with multiple opportunistic infections and were associated with an adult-onset immunodeficiency akin to that of advanced HIV infection. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research; ClinicalTrials.gov number, NCT00814827.).

Rhinofacial entomophthoramycosis; a case series and review of the literature.

Rhinofacial entomophthoramycosis is an uncommon chronic mycotic disease caused by exposure to the organism Conidiobolus coronatus. The authors report a case series of 5 patients with rhinofacial entomophthoramycosis and review the literature. All patients had typical involvement of the rhinofacial area with formation of subcutaneous lesions causing a chronic granulomatous inflammatory response with tissue eosinophilia and Splendore-Hoeppli reaction. Diagnoses were made based on histopathologic examination in all cases and fungi were isolated and identified in one case. The clinicopathologic features and therapeutic management of rhinofacial entomophthoramycosis are described.

A model and risk score for predicting nevirapine-associated rash among HIV-infected patients: in settings of low CD4 cell counts and resource limitation.

BACKGROUND: Rash is the most common adverse effect associated with nevirapine (NVP). We aimed to develop a model and risk score for predicting NVP-associated rash among HIV-infected patients with low CD4 cell counts. METHODS: Cross-sectional study was conducted and 383 HIV-infected patients consecutively enrolled in the study. RESULTS: Of 222 patients in the training set, 116 (52.2%) were males and median (IQR) age was 35.2 (31.1-42.0) years. Median (IQR) CD4 cell count was 104 (35-225) cells/mm(3). Of these, 72 and 150 patients were in "rash" and "no rash" group, respectively. Four factors were independently associated with rash: a history of drug allergy (odds ratio (OR) 4.01, 95% confidence interval (CI), 1.75-9.20, P = 0.001), body weight <55 kg. (OR 2.02, 95% CI, 1.09-3.76, p = 0.026), not receiving slow dose escalation (OR 2.00, 95% CI, 1.06-3.77, p = 0.032), and no concomitant drug(s) (OR 2.48, 95% CI, 1.32-4.64, p = 0.005). Receiver-operator characteristic analysis yielded area under the curve of 71% and the goodness-of-fit statistics was 6.48 (p = 0.840). The variables were given scores of 14, 7, 7 and 9, respectively. A cutoff >21 points defined the high risk individuals which yielded specificity and positive predictive value of 99% and 69%, respectively, with OR of 3.96 (95% CI, 1.79-8.86, p = 0.001). CONCLUSIONS: A model and risk score for predicting NVP-associated rash performed well in this study population. It might be useful for predicting the risk of rash before NVP initiation among HIV-infected patients with low CD4 cell counts.

HIV-1 genotype after interruption of non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy and virological response after resumption of the same regimen.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have a longer half-life than nucleoside reverse transcriptase inhibitor (NRTIs). Simultaneous interruption of all drugs exposes the patients to NNRTI monotherapy. This study evaluated HIV-1 genotype after treatment interruption (TI) of NNRTI-based antiretroviral therapy (ART) and virological response after resumption of the same ART regimen. A prospective study was conducted in HIV-1-infected patients who enrolled into a CD4-guided TI study. All patients continued dual NRTIs for a further 7-10 days at NNRTI TI. HIV-1 genotypic assay was performed prior to resumption of the same ART regimen. Forty-three patients required ART resumption after TI from NNRTI-based regimens. Mean age was 42.7 years; 44% were men. Median CD4 and HIV-1 RNA at the time of ART resumption were 178 cell/mm(3) and 5.78 log copies/mL, respectively. HIV-1 genotype revealed no mutations contributed to NRTI or NNRTI resistance. Of all, 56% and 100% patients achieved undetectable HIV-1 RNA at three and six months, respectively. Median CD4 were 386 and 419 cells/mm(3) at the corresponding periods. In conclusion, continuation of dual NRTIs for 7-10 days after TI of NNRTI-based regimens can minimize the risk of acquired NNRTI resistance. With this strategy, the same regimen can be used for resumption and also yield good virological and immunological outcomes.

Rapid CD4 decline after interruption of non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy in a resource-limited setting.

BACKGROUND: Non-nucleoside reverse transcriptase inhibitor (NNRTI) with stavudine and lamivudine is widely used as the first-line antiretroviral therapy (ART) in resource-limited settings. Lipodystrophy is common and options for switching ART regimen are limited; this situation can lead to patients' poor adherence and antiretroviral resistance. Treatment interruption (TI) in patients with high CD4 cell counts, lipodystrophy, and limited options may be an alternative in resource-limited settings. This study aimed to determine time to resume ART after TI and predictors for early resumption of ART in a resource-limited setting. METHODS: A prospective study was conducted in January 2005 to December 2006 and enrolled HIV-infected patients with HIV-1 RNA <50 copies/mL, CD4 > 350 cells/mm3, and willing to interrupt ART. CD4 cell count, HIV-1 RNA, lipid profile, and lipodystrophy were assessed at baseline and every 3 months. ART was resumed when CD4 declined to <250 cells/mm3 or developed HIV-related symptoms. Patients were grouped based on ART regimens [NNRTI or protease inhibitor (PI)] prior to TI. RESULTS: There were 99 patients, 85 in NNRTI group and 14 in PI group. Mean age was 40.6 years; 46% were males. Median duration of ART was 47 months. Median nadir CD4 and baseline CD4 were 151 and 535 cells/mm3, respectively. Median CD4 change at 3 months after TI were -259 (NNRTI) and -105 (PI) cells/mm3 (p = 0.038). At 13-month median follow-up, there was no AIDS-defining illness; 38% (NNRTI) and 29% (PI) of patients developed HIV-related symptoms. ART was resumed in 51% (NNRTI) and 36% (PI) of patients (p = 0.022). By Kaplan-Meier analysis, median time to resume ART was 5.5 (NNRTI) and 14.2 (PI) months (log rank test, p = 0.026). By Cox's regression analysis, NNRTI-based ART (HR 4.9; 95%CI, 1.5-16.3), nadir CD4 <100 cells/mm3 (HR 2.7; 95%CI 1.4-5.3) and baseline CD4 <500 cells/mm3 (HR 1.6; 95%CI, 1.2-3.1) were predictors for early ART resumption. CONCLUSION: TI of NNRTI-based ART leads to rapid CD4 decline and high probability of early ART resumption and should be avoided. It is necessary to scale-up the options for HIV-infected patients with lipodystrophy in resource-limited settings.

Logistic regression analysis to predict Medical Licensing Examination of Thailand (MLET) Step1 success or failure.

INTRODUCTION: The aim of this paper was to assess factors that predict students' performance in the Medical Licensing Examination of Thailand (MLET) Step1 examination. The hypothesis was that demographic factors and academic records would predict the students' performance in the Step1 Licensing Examination. MATERIALS AND METHODS: A logistic regression analysis of demographic factors (age, sex and residence) and academic records [high school grade point average (GPA), National University Entrance Examination Score and GPAs of the pre-clinical years] with the MLET Step1 outcome was accomplished using the data of 117 third-year Ramathibodi medical students. RESULTS: Twenty-three (19.7%) students failed the MLET Step1 examination. Stepwise logistic regression analysis showed that the significant predictors of MLET Step1 success/failure were residence background and GPAs of the second and third preclinical years. For students whose sophomore and third-year GPAs increased by an average of 1 point, the odds of passing the MLET Step1 examination increased by a factor of 16.3 and 12.8 respectively. The minimum GPAs for students from urban and rural backgrounds to pass the examination were estimated from the equation (2.35 vs 2.65 from 4.00 scale). CONCLUSIONS: Students from rural backgrounds and/or low-grade point averages in their second and third preclinical years of medical school are at risk of failing the MLET Step1 examination. They should be given intensive tutorials during the second and third pre-clinical years.

Evidence-based medicine in clinical curriculum.

INTRODUCTION: The teaching of evidence-based medicine (EBM) has now been incorporated as an integral part of medical curriculum at the Faculty of Medicine, Ramathibodi Hospital but there is little research into the effectiveness of the course. The purpose of this report is to evaluate the EBM skills of medical students and competency of the faculty member. MATERIALS AND METHODS: The EBM course was created by the EBM Working Group at the Faculty of Medicine, Ramathibodi Hospital for 3rd- to 6th-year medical students. The principles of EBM, clinical epidemiology and biostatistics were gradually instilled during the 4 years of medical school. Information technology infrastructure was also provided to facilitate critical appraisal skills. At the end of the Community Medicine clerkship, students anonymously evaluated aspects of the course regarding their EBM skills and faculty member competency with Likert scale questions. RESULTS: Medical students generally gave high evaluations to all aspects of the EBM course taught in the Community Medicine Department. For each of the evaluation questions, the means were higher for faculty member competency. CONCLUSIONS: The teaching of EBM course at the Faculty of Medicine, Ramathibodi Hospital is useful for medical students to enhance their critical thinking skills, and they seem to value the sessions positively.

Clinical and epidemiological analyses of human pythiosis in Thailand.

BACKGROUND: Pythiosis is an emerging and life-threatening infectious disease in humans and animals that is caused by the pathogenic oomycete Pythium insidiosum. Human pythiosis is found mostly in Thailand, although disease in animals has been increasingly reported worldwide. Clinical information on human pythiosis is limited, and health care professionals are unfamiliar with the disease, leading to underdiagnosis, delayed treatment, and poor prognosis. METHODS: To retrospectively study the clinical and epidemiological features of human pythiosis, we analyzed clinical data from patients with pythiosis diagnosed during the period of January 1985 through June 2003 at 9 tertiary care hospitals throughout Thailand. RESULTS: A total of 102 cases of human pythiosis were documented nationwide. A substantial proportion (40%) of cases occurred in the last 4 years of the 18-year study interval. Clinical presentations fell into 4 groups: cutaneous/subcutaneous cases (5% of cases), vascular cases (59%), ocular cases (33%), and disseminated cases (3%). Almost all patients with cutaneous/subcutaneous, vascular, and disseminated pythiosis (85%) had underlying thalassemia-hemoglobinopathy syndrome. Most ocular cases (84%) were associated with no underlying disease. A majority of the patients were male (71%), were aged 20-60 years (86%), and reported an agricultural occupation (75%). Regarding treatment outcomes, all patients with disseminated infection died; 78% of patients with vascular disease required limb amputation, and 40% of these patients died; and 79% of patients with ocular pythiosis required enucleation/evisceration. CONCLUSIONS: Here, we report, to our knowledge, the largest case study of human pythiosis. The disease has high rates of morbidity and mortality. Early diagnosis and effective treatment are urgently needed to improve clinical outcomes. Because P. insidiosum is distributed worldwide and can infect healthy individuals, an awareness of human pythiosis should be promoted in Thailand and in other countries.

Identification of a novel 74-kiloDalton immunodominant antigen of Pythium insidiosum recognized by sera from human patients with pythiosis.

The oomycetous, fungus-like, aquatic organism Pythium insidiosum is the etiologic agent of pythiosis, a life-threatening infectious disease of humans and animals that has been increasingly reported from tropical, subtropical, and temperate countries. Human pythiosis is endemic in Thailand, and most patients present with arteritis, leading to limb amputation and/or death, or cornea ulcer, leading to enucleation. Diagnosis of pythiosis is time-consuming and difficult. Radical surgery is the main treatment for pythiosis because conventional antifungal drugs are ineffective. The aims of this study were to evaluate the use of Western blotting for diagnosis of human pythiosis, to identify specific immunodominant antigens of P. insidiosum, and to increase understanding of humoral immune responses against the pathogen. We performed Western blot analysis on 16 P. insidiosum isolates using 12 pythiosis serum samples. These specimens were derived from human patients with pythiosis who had different forms of infection and lived in different geographic areas throughout Thailand. We have identified a 74-kDa immunodominant antigen in all P. insidiosum isolates tested. The 74-kDa antigen was also recognized by sera from all patients with pythiosis but not by control sera from healthy individuals, patients with thalassemia, and patients with various infectious diseases, indicating that Western blot analysis could facilitate diagnosis of pythiosis. Therefore, the 74-kDa antigen is a potential target for developing rapid serodiagnostic tests as well as a therapeutic vaccine for pythiosis. These advances could lead to early diagnosis and effective treatment, crucial factors for better prognosis for patients with pythiosis.

Efficacy of immunotherapy using antigens of Pythium insidiosum in the treatment of vascular pythiosis in humans.

Human pythiosis is an emerging disease in the tropical, subtropical and temperate regions of the world. It is caused by the straminipilan, fungus-like, aquatic organism Pythium insidiosum. Pythiosis occurs in localized as well as systemic or vascular forms. Most patients with arterial pythiosis usually have underlying hematologic disorders such as thalassemia and aplastic anemia/paroxysmal nocturnal hemoglobinuria (PNH) syndrome. Vascular pythiosis is characterized by ascending blood vessel infections and thrombosis of the major arteries especially those of the lower extremities. When the infection reaches a main artery, the patient usually dies within weeks. Since this pathogen is resistant to most antifungal drugs, immunotherapy was recently used to cure humans and animals with the disease. A modified P. insidiosum-antigen (PIA) formulation had already saved a young boy with life-threatening arterial pythiosis. Here, we report the therapeutic benefits of the PIA in eight patients with vascular pythiosis. Six of them had thalassemia and the other two had PNH. All of the patients had arterial occlusion of the lower limbs. P. insidiosum was isolated and identified by culture and by histopathology. All patients had evidence of active infection when immunotherapy began. After two injections of 100-200 microl of PIA (2.0mg/ml), at a 14-day interval, four patients (50%) had dramatic and complete remission. Two patients showed partial responses to PIA while the other two did not. Clinical responses correlated with the immunological reactions at the site of injection, clearance of the arteries and cytokine production. The latter included the shifting in serum levels of IL4 and IL5 to IL2 suggesting a switching from a T helper 2 (Th2) to a T helper 1 (Th1) subset. Our findings provide further evidence that immunotherapy using PIA is a safe and effective method to treat pythiosis in humans.

Sweet's syndrome: a reaction to non-tuberculous mycobacterial infections.

Sweet's syndrome has been reported to be associated with many underlying conditions, such as non-tuberculous mycobacterial infections (NTMI). In the literature, only twelve patents with Sweet's syndrome in association with NTMI have been reported (most of the patients were from Thailand). Here, the authors report six more patients who developed Sweet's syndrome as a reaction to NTMI. Four patients had Mycobacterium chelonae/abscessus group infection; one patient had been infected with Mycobacterium avium complex first and became infected with M. chelonae/abscessus group 17 months later; and, the other one had Mycobacterium fortuitum infection. In each patient, the skin lesions of Sweet's syndrome relapsed many times while they still had NTMI, and these lesions usually responded well to short courses of systemic steroids without any deterioration of NTMI.

Infections with rapidly growing mycobacteria: report of 20 cases.

OBJECTIVES: A series of cases infected with rapidly growing mycobacteria was studied to determine the spectrum of disease, antimicrobial susceptibility, treatment, and outcome. METHODS: The cases identified as infections with rapidly growing mycobacteria in Ramathibodi Hospital from January 1993 to December 1999 were retrospectively studied. RESULTS: Most of the cases had no underlying disease. Only two cases were HIV-infected patients. The presenting clinical features were lymphadenitis (seven cases), skin and/or subcutaneous abscess (seven cases), localized eye infection (four cases), pulmonary infection (one case), and chronic otitis media (one case). Four of seven cases with lymphadenitis had Sweet's syndrome, and one had psoriasis as an associated skin manifestation. Anemia was present in five cases, and improved with treatment of the primary disease. The organisms were Mycobacterium chelonae/abscessus group (17 cases) and Mycobacterium fortuitum group (three cases). Susceptibility patterns of the organisms showed susceptibility to amikacin, netilmicin, and imipenem. M. fortuitum group was susceptible to more antibiotics than M. chelonae/abscessus group. The clinical responses corresponded to the antimicrobial susceptibility. Combinations of two or more drugs were used for the medical treatment. Surgical resection was performed where possible, to reduce the load of the organism, especially in cases with very resistant organisms. CONCLUSIONS: Infections with rapidly growing mycobacteria can occur in apparently normal hosts. The clinical syndrome is variable. The pathology is nonspecific. Clinical responses varied, but seemed to correlate with the in vitro susceptibility result. More studies are needed to enable us to deal with this infection effectively.

Utilization of restricted antibiotics in a university hospital in Thailand.

Antibiotic resistance, a major negative consequence of antibiotic overuse, is an important problem worldwide. Various means have been used to control antibiotic usage including the use of an antibiotic order form (AOF), restricted antibiotic formularies and provision of educational information. The present study was designed to evaluate the use of antimicrobials in a 1,000-bed university hospital. Antimicrobial agents, likely to be abused namely ceftazidime, cefepime, cefoperazone/sulbactam, imipenem/cilastatin, meropenem, ciprofloxacin, netilmicin, vancomycin, azithromycin and clarithromycin, were selected for evaluation. A simple AOF with educational information was used as a mean to follow up the treatment. The investigator collected data from the filled AOF and the patient's charts of the Department of Internal Medicine from June to November 2000; all relevant data were assessed. The appropriateness of antibiotic use, assessed according to the criteria specified in the AOF, showed that 74% of these antibiotics were prescribed appropriately; this may prove the effectiveness of the system used in the present study. However, 348 of the 430 prescriptions (80.9%) were prescribed empirically at the initial stage for treatment of nosocomial infections in patients with serious conditions like pneumonia, sepsis and febrile neutropenia. Drugs that were frequently used empirically were ceftazidime (37.9%), imipenem/cilastatin or meropenem (19.3%), and cefoperazone/sulbactam (12.1%) respectively. Ceftazidime and imipenem/cilastatin or meropenem were also frequently used inappropriately among 111 prescriptions that were classified as an inappropriate prescribing. The most common misuses were prescriptions of the drug that did not follow the specified indications (70 prescriptions), no dosage adjustment in patients with renal impairment (39 prescriptions), improper dose (12 prescriptions) and improper dosing interval (9 prescriptions). The results suggested overuse of certain antibiotics remain to be an unsolved problem. Better monitoring and strict controlled use of the problematic antibiotics, ie ceftazidime, imipenem/cilastatin or meropenem and vancomycin are essential to promote rational drug use as well as to reduce the frequency of drug resistance.

Rapidly growing mycobacterial infections: spectrum of diseases, antimicrobial susceptibility, pathology and treatment outcomes.

OBJECTIVES: A series of cases infected with rapidly growing mycobacteria were studied to reveal the spectrum of disease, antimicrobial susceptibility, pathology, and treatment outcomes. METHOD: The cases identified as rapidly growing mycobacterial infections in Ramathibodi Hospital from January 1993 to June 1999 were retrospectively studied. RESULTS: There were 20 patients and most of the cases had no underlying disease. Only two cases were HIV-infected patients. The presenting clinical features were lymphadenitis (7), skin and subcutaneous abscess (7), eye infection (4), pulmonary infection (1), and chronic otitis media (1). Four of the seven cases with lymphadenitis had Sweet's syndrome. The organisms were Mycobacterium chelonae/abscessus group (17 cases) and Mycobacteriumfortuitum group (3 cases). The organisms were susceptible to amikacin, netilmicin and imipenem. The M. fortuitum group was susceptible to more antibiotics than the M. chelonaelabscessus group. Pathology of the infected tissue varied from non-specific findings to suppurative or caseous granuloma. The clinical responses corresponded to the antimicrobial susceptibility. Most of the patients had a good clinical outcome. A combination of two or more drugs was used for the medical treatment. Surgical resection was performed where possible to reduce the load of the organism, especially in cases with very resistant organisms. CONCLUSIONS: Rapidly growing mycobacterial infections can occur in apparently normal hosts. Clinical syndrome is variable. The pathology is non-specific and culture is needed for definite diagnosis. Clinical responses varied but seemed to correlate with the in vitro susceptibility result. More studies are needed before one can deal with these infections more effectively.