A pilot study of N-acetylcysteine as adjunctive therapy for severe malaria.

BACKGROUND: The case fatality rate of severe malaria remains unacceptably high. N-acetylcysteine (NAC) is a safe compound that inhibits tumour necrosis factor (TNF) and impedes cytoadherence, both of which have been implicated in the pathogenesis of malaria complications. AIM: To evaluate NAC as adjunctive therapy in severe malaria. DESIGN: A placebo-controlled, double-blind prospective study, with serum lactate level as the principal objective measure of response. METHODS: Thirty adult males with severe, quinine-treated malaria received either 300 mg/kg of NAC or placebo, over 20 h. RESULTS: Serum lactate levels normalized twice as quickly after NAC (median 21 h, 95%CI 12-36 h) as after placebo (median 42 h, 95%CI 30-84 h; p=0.002, Mann-Whitney U test). Twenty-four hours after admission, 10/15 (67%) NAC-group patients but only 3/15 (20%) placebo-group patients had normal lactate concentrations (p=0.01, Fisher exact test). NAC-treated patients could be switched from intravenous to oral therapy earlier than individuals who received placebo (42 h vs. 51 h after admission) but the difference was not significant (p=0.28, Mann-Whitney U test). DISCUSSION: NAC's mechanism of action in malaria is unclear, since it did not markedly alter plasma cytokine profiles. Trials of NAC adjunctive therapy for complicated malaria, with mortality as an endpoint, appear to be warranted.

Passive transfer of scrub typhus plasma to patients with AIDS: a descriptive clinical study.

We examined the HIV-inhibitory effects previously found to be associated with scrub typhus infection. Individual 500 ml units of plasma from donors with mild scrub typhus were safety-tested, subjected to virucidal heat treatment, and administered to 10 HIV-1-infected recipients who were not receiving antiretroviral drugs. HIV-1 copy number fell three-fold or more in two recipients, and virus burden was reduced for 8 weeks in 70% (7/10) of recipients of a single plasma infusion, compared with the mean of three pre-infusion measurements. Scrub typhus donor plasma inhibited HIV-1 in vitro compared with normal human plasma and media controls. In the clearest in vivo response, reduction in viral load was accompanied by clinical improvement, a switchback from the syncytia-inducing to the non-syncytia-inducing phenotype, and decreases in CD8 cells and IL-6 levels. Scrub typhus infections can generate heat-stable, transferable plasma factors that exert prolonged anti-HIV effects. Whether variability in the results is due to different scrub typhus infections, different HIV infections or different individual responses, is unclear.

Hand rash in trichinosis.

Trichinosis patients may develop peri-orbital oedema, conjunctival haemorrhages, splinter haemorrhages of the fingernails, and nonspecific skin rashes. Here, we describe an unusual hand rash noted in several patients enrolled in a treatment study for trichinosis.

Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria.

The single-dose pharmacokinetics of 100 mg of orally administered artesunate (AS) were studied in 6 patient volunteers with uncomplicated falciparum malaria and in 6 healthy volunteers. Plasma concentrations of both the parent drug, AS, and its major metabolite, dihydroartemisinin (DHA), were measured simultaneously by high-performance liquid chromatography (HPLC) with electrochemical detection (ECD). The antimalarial activity of each plasma sample measured by an in vitro bioassay (BA) was used to derive activity concentrations. Artesunate was absorbed rapidly and then almost completely hydrolyzed to DHA in patients, whereas hydrolysis was incomplete in healthy volunteers. The mean +/- standard deviation (SD) maximum concentration (Cmax) of AS was 296+/-110 nmol/L, the time to peak blood level (tmax was 0.71+/-0.66 hr, the half-life (t1/2,z) was 0.41+/-0.34 hr, and the bioavailability over 12 hr (area under the curve [AUC](0-12)) was 253+/-185 nmol hr/L. Measured by HPLC, the Cmax and AUC(0-12) values of DHA in patients with malaria were significantly greater than in volunteers (1,948+/-772 and 1,192+/-315 nmol/L; 4,024+/-1,585 and 1,763+/-607 nmol hr/L, respectively; P < or = 0.05). These differences were even greater when measured by BA. The Cmax for patients with malaria was 2,894+/-2,497 and 795+/-455 nmol/L for volunteers, and AUC(0-12) was 5,970+/-3,625 and 1,307+/-391 nmol hr/L, respectively (P < or = 0.05). In contrast, DHA parameter estimates for t1/2,z and tmax were similar between patients and healthy volunteers, with values of 0.80+/-0.30 versus 0.87+/-0.06 hr and 1.50+/-0.55 versus 1.13+/-0.52 hr, respectively (P > 0.5). Both drug metabolism and tissue protein binding could contribute to the differences between the antimalarial activity of artemisinin drugs in healthy volunteers and malaria infected patients.

Orientia tsutsugamushi in peripheral white blood cells of patients with acute scrub typhus.

Scrub typhus, caused by Orientia tsutsugamushi, is an acute illness that occurs in many parts of Asia. Clinical manifestations range from inapparent to organ failure. Organisms disseminate from the skin to target organs, suggesting that they may enter the peripheral circulation. Here, peripheral blood cell smears from patients with acute scrub typhus were obtained before treatment and for 2 days after treatment and reacted with antibodies specific for O. tsutsugamushi. White blood cells from 3 of 7 patients with acute scrub typhus stained positively for O. tsutsugamushi. Cells containing O. tsutsugamushi were mononuclear and were detected on each day of sampling. The presence of O. tsutsugamushi in peripheral white blood cells of patients with acute scrub typhus is a new finding with clinical and pathogenic implications.

Doxycycline and rifampicin for mild scrub-typhus infections in northern Thailand: a randomised trial.

BACKGROUND: Some strains of scrub typhus in northern Thailand are poorly responsive to standard antirickettsial drugs. We therefore did a masked, randomised trial to compare rifampicin with standard doxycycline therapy for patients with scrub typhus. METHODS: Adult patients with strictly defined, mild scrub typhus were initially randomly assigned 1 week of daily oral treatment with 200 mg doxycycline (n=40), 600 mg rifampicin (n=38), or doxycycline with rifampicin (n=11). During the first year of treatment, the combined regimen was withdrawn because of lack of efficacy and the regimen was replaced with 900 mg rifampicin (n=37). Treatment outcome was assessed by fever clearance time (the time for oral temperature to fall below 37.3 degrees C). FINDINGS: About 12,800 fever patients were screened during the 3-year study to recruit 126 patients with confirmed scrub typhus and no other infection, of whom 86 completed therapy. Eight individuals received the combined regimen that was discontinued after 1 year. The median duration of pyrexia was significantly shorter (p=0.01) in the 24 patients treated with 900 mg daily rifampicin (fever clearance time 22.5 h) and in the 26 patients who received 600 mg rifampicin (fever clearance time 27.5 h) than in the 28 patients given doxycycline monotherapy (fever clearance time 52 h). Fever resolved in a significantly higher proportion of patients within 48 h of starting rifampicin (900 mg=79% [19 of 24], 600 mg=77% [20 of 26]) than in patients treated with doxycycline (46% [13 of 28]; p=0.02). Severe gastrointestinal events warranted exclusion of two patients on doxycyline. There were two relapses after doxycycline therapy, but none after rifampicin therapy. INTERPRETATION: Rifampicin is more effective than doxycycline against scrub-typhus infections acquired in northern Thailand, where strains with reduced susceptibility to antibiotics can occur.

HIV-1 suppression during acute scrub-typhus infection.

BACKGROUND: In HIV-1-infected individuals, viral load has been reported to rise transiently if an acute infection with another organism occurs. Our study was prompted by the unexpected finding that HIV-1 copy number fell during an acute infection with Orientia tsutsugamushi, the causative agent of scrub typhus. METHODS: Serial HIV-1 viral load determinations were made in ten Thai adults with scrub typhus, who were not receiving antiretroviral therapy, and in five HIV-1-infected patients who had other infections (four malaria, one leptospirosis), during and after acute infections. Sera from HIV-1-infected patients with scrub typhus and from mice immunised with O. tsutsugamushi were examined for HIV-1-suppressive activity. FINDINGS: Median viral load 3 days after admission was significantly lower in the scrub-typhus group than in patients with other infections (193% vs 376% of day 28 values, p=0.03). In four O. tsutsugamushi-infected patients HIV-1 RNA copy number fell by three-fold or more compared with day 28 values, and HIV-1 copy numbers were below the assay threshold in two patients with scrub typhus. Five of seven HIV-1 isolates from non-typhus patients with CD4 lymphocytes less than 200 cells/microL were syncytia-inducing variants, whereas all ten isolates from O. tsutsugamushi-infected individuals matched by CD4-cell count were non-syncytia inducing (p=0.03). Sera from an HIV-1-negative patient with scrub typhus had potent HIV-1-suppressive activity in vitro. Sera from typhus-infected mice inhibited HIV-1 syncytia formation and bound by immunofluorescence to HIV-1-infected lymphocytes. INTERPRETATION: HIV-1-suppressive factors are produced during some scrub-typhus infection and should be investigated further in the search for novel strategies for the treatment and prevention of AIDS.

Blinded, placebo-controlled trial of antiparasitic drugs for trichinosis myositis.

There is no consensus on the benefits of treatment with any specific anthelminthic compound on muscle-stage trichinosis. A double-blind, placebo-controlled comparison was done of 3 antiparasitic drugs during an outbreak of trichinosis in Chiangrai Province, northern Thailand. Forty-six adults were randomized to receive 10 days of oral treatment with mebendazole (200 mg twice a day), thiabendazole (25 mg/kg twice a day), fluconazole (400 mg initially, then 200 mg daily), or placebo. All patients received treatment to eradicate adult intestinal worms. Trichinella spiralis infection was proved parasitologically in 19 (41%) of 46 patient and by serodiagnosis in all cases. Significantly more patients improved after treatment with mebendazole (12/12) and thiabendazole (7/7) than after treatment with placebo (6/12; P<.05) or fluconazole (6/12). Muscle tenderness resolved in more patients treated with thiabendazole and mebendazole than in those treated with placebo (P<.05). However, 30% of volunteers could not tolerate the side effects of thiabendazole. In summary, Trichinella myositis responds to thiabendazole and to mebendazole.

Azithromycin activities against Orientia tsutsugamushi strains isolated in cases of scrub typhus in Northern Thailand.

Azithromycin was given to mice and humans infected with strains of Orientia tsutsugamushi from northern Thailand, where drug-resistant scrub typhus occurs. Azithromycin and doxycycline yielded comparable mouse survival rates (73 and 79%, respectively; P > 0.5). Symptoms, signs, and fever in two pregnant women abated rapidly with azithromycin. Prospective human trials are needed.

Thai language skill and HIV counseling among hilltribe people: a hospital-based study in Chiang Rai.

Twenty-nine hilltribe individuals from 6 different ethnic groups were among a group of 70 patients included in an investigation of interactions between HIV-1 virus infection and common tropical illnesses. Approximately half of the hilltribe subjects (14/29) required the aid of an interpreter for HIV counseling because they could neither speak nor understand the Thai language. The 5 HIV seropositive hilltribe individuals were younger than their seronegative counterparts (26 vs 37 years respectively; p < 0.05) and had less need of an interpreter (0% vs 58% respectively; p < 0.05). Inability to speak and understand Thai limits the access of some ethnic minority subjects to HIV counseling, testing and education.

Performance of a dot blot immunoassay for the rapid diagnosis of scrub typhus in a longitudinal case series.

A rapid dipstick test for scrub typhus was prospectively evaluated in Chiangrai, northern Thailand. Sera from 162 patients with fever of unclear etiology were tested by a dot blot immunoassay using two different antigen concentrations. Dipsticks coated with lower concentration of antigen lacked sensitivity compared with the indirect immunoperoxidase test. Dipsticks with higher antigen concentration had increased sensitivity that was equivalent to that of the immunoperoxidase test. By increasing the antigen concentration on the dipstick, sensitivity increased from 67% to 100%, positive predictive value increased from 90% to 93%, and negative predictive value rose from 92% to 100%. The specificity of both antigen concentrations was 98%. This study establishes that scrub typhus can be confirmed serologically by use of a dipstick assay and that serodiagnosis can be effectively tailored to a target population.

Infection with human immunodeficiency virus does not influence the clinical severity of scrub typhus.

Infection by Orientia (formerly Rickettsia) tsutsugamushi causes scrub typhus, a severe febrile disease common in Asia. Both scrub typhus and AIDS are prevalent in northern Thailand. Therefore, we prospectively investigated the impact of infection due to human immunodeficiency virus (HIV) on the severity of the clinical syndrome produced by O. tsutsugamushi. The severity of scrub typhus was objectively graded on admission of patients to the hospital, and serologies for antibodies to HIV were performed. Fourteen (16%) of 86 patients with scrub typhus were infected with HIV; the median T helper cell count was 70/mm3. There were no significant differences between HIV-infected patients and non-HIV-infected patients in severity scores or other admission characteristics. O. tsutsugamushi was isolated in blood samples from 48.6% of patients without HIV infection and in blood samples from 14.3% of HIV-infected patients (P < .05 x 2 test). The clinical manifestations of O. tsutsugamushi infection, unlike those due to some other intracellular pathogens, are not unusually severe in immunocompromised patients with AIDS.

Scrub typhus infections poorly responsive to antibiotics in northern Thailand.

BACKGROUND: Rickettsia tsutsugamushi, the aetiological agent of scrub typhus, is common in Asia and readily infects visitors to areas where disease transmission occurs. Rapid defervescence after antibiotic treatment is so characteristic that it is used as a diagnostic test for R tsutsugamushi infection. Reports from local physicians that patients with scrub typhus in Chiangrai, northern Thailand responded badly to appropriate antibiotic therapy prompted us to do a prospective clinical evaluation and antibiotic susceptibility testing of human rickettsial isolates. METHODS: The clinical response to doxycycline treatment in patients with early, mild scrub typhus in northern Thailand was compared with the results of treatment in Mae Sod, western Thailand. Prototype and naturally occurring strains of R tsutsugamushi were tested for susceptibility to chloramphenicol and doxycycline in mice and in cell culture. FINDINGS: By the third day of treatment, fever had cleared in all seven patients from Mae Sod, but in only five of the 12 (40%) from Chiangrai (p < 0.01). Median fever clearance time in Chiangrai (80 h; range 15-190) was significantly longer than in Mae Sod (30 h; range 4-58; p < 0.005). Conjunctival suffusion resolved significantly more slowly in Chiangrai (p < 0.05). Antibiotics prevented death in mice infected by Chiangrai strains of R tsutsugamushi less often than after infection by the prototype strain (p < 0.05). Only one of three Chiangrai strains tested in cell culture was fully susceptible to doxycycline. INTERPRETATION: Chloramphenicol-resistant and doxycycline-resistant strains of R tsutsugamushi occur in Chiangrai, Thailand. This is the first evidence of naturally occurring antimicrobial resistance in the genus Rickettsia.

Immunodiagnosis of trichinellosis: efficacy of somatic antigen in early detection of human trichinellosis.

Crude antigens prepared from the infective stage larvae of Trichinella spiralis were used for antibody detection by indirect ELISA and Western blotting in serum samples taken from trichinellosis patients and from normal, parasite-free controls. The serum specimens were collected from acute ill, symptomatic patients on the first day of treatment (Day 0), and then two months (M2) and 4 months (M4) later. The sensitivities of the indirect ELISA and Western blotting on Day 0 were 81% and 92%, respectively. Both tests were 100% sensitive for M2 and M4 serum samples. Every serum sample from the parasite-free controls tested negative by both immunological assays, indicating 100% specificity. Crude somatic antigens can therefore be used for the early detection of human trichinellosis (acute trichinellosis).

Efficacy and tolerance of extended-dose halofantrine for drug-resistant falciparum malaria in Thailand.

New treatments for malaria are urgently needed in areas such as Thailand where highly drug-resistant strains of Plasmodium falciparum are prevalent. Mefloquine is rapidly losing efficacy and conventional doses of halofantrine are infective. We therefore used pharmacokinetic stimulation to design an extended-dose halofantrine regimen and tested it in 26 soldiers stationed along the Thai-Cambodian border. Halofantrine was given after meals as three doses of 500 mg each at 4-hr intervals on the first day, followed by 500 mg a day for six days (total dose 4.5 g). Twenty-six soldiers treated with quinine-tetracycline for seven days (Q7T7) served as controls. There were no significant differences in efficacy between halofantrine and Q7T7 (P > 0.1) as assessed by cure rate (92% versus 85%), mean parasite clearance time (82 hr versus 81 hr), or mean fever clearance time (93 hr versus 99 hr). Halofantrine was better tolerated than Q7T7. The side effects score was lower (2 versus 11; P < 0.001), there were less days on which side effects occurred (2.0 days versus 5.5 days; P < 0.001), and fewer patients had adverse effects on every treatment day (4% versus 42%; P < 0.01). High-dose halofantrine is as effective and better tolerated than quinine-tetracycline for multidrug-resistant falciparum malaria.

Glucose-6-phosphate dehydrogenase deficiency in Thailand: the influence on the clinical presentation of malaria in male adult patients.

One hundred and ninety-two male malaria patients admitted to two different hospitals within 1 year, were studied. There were 74 malaria cases with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and 118 G-6-PD normal malaria cases, randomly selected as a control group. History of dark urine, and the presence of jaundice, haematocrit, total bilirubin and parasite count on day of admission were not significantly different comparing both groups. The number of observed complications did not differ either. Distinctions were detected in abnormal symptoms and in some laboratory parameters in patients with Plasmodium falciparum infection. G-6-PD deficient patients had significantly less gastrointestinal disturbances (P = 0.006), higher serum glutamic oxalacetic transaminase (P = 0.009) and significantly lower blood urea nitrogen (P = 0.007) when compared with the control group. These findings indicate that G-6-PD deficiency when the variants are aggregated, in male adult patients has no significant influence on the clinical presentation of malaria.