Search

Background: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis., Methods: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated., Results: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%)., Conclusions: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

There have been significant advances in both the classical and neglected tropical diseases, with Guinea worm looking set to be the next disease after smallpox to be eradicated. Aided by a combination of enhanced understanding of the biology of the pathogens, intensification of immunisation activities or mass drug administration, together with the development of synergies with control programmes for co-endemic tropical diseases, polio, lymphatic filariasis, trachoma and onchocerciasis all appear to be in global decline, with good prospects for eventual successful elimination. While the global incidence of new cases of leprosy continues to decrease, the focus of leprosy control efforts has shifted following more widespread recognition that cure of infection does not necessarily prevent disability. Expansion in funding for HIV/AIDS and malaria provides some grounds for optimism about the control of these diseases. However, ongoing education and access remain essential to increasing the uptake of HIV testing and decreasing transmission. Meanwhile, the rise of drug-resistant tuberculosis and malaria is concerning, and the emergence of the highly pathogenic avian influenza A and re-emergence of viruses such as chikungunya and West Nile virus, without significant recent progress in vaccine development, pose additional ongoing challenges to tropical medicine physicians worldwide.

Background: Over a 16-year period, we conducted a clinical study of malaria acquired worldwide in adults from malaria-nonendemic countries, to determine risk factors for severe Plasmodium falciparum malaria., Methods: All patients with confirmed malaria who were managed by our unit from 1991 to 2006 were prospectively evaluated. Factors predicting disease severity according to (1) strict World Health Organization (WHO) criteria, (2) a composite measure of unfavorable outcome, and (3) length of hospital stay were identified by logistic and linear regression analyses., Results: We evaluated 676 episodes of malaria, 482 (71%) due to P. falciparum and 194 (29%) due to nonfalciparum parasites. Black patients had a significantly reduced risk of developing WHO-defined severe falciparum malaria, with Asian patients having odds of severe falciparum malaria that were 8.05-fold (95% confidence interval [CI], 2.93-22.1-fold) higher and white patients having odds that were 8.20-fold (95% CI, 2.94-22.9-fold) higher. Black patients also had a reduced risk of an unfavorable outcome and of a prolonged stay in the hospital, compared with the risks for white or Asian patients. Of 6 patients with falciparum malaria who died, none were black. In univariate analysis, patients with parasitemias of >or= 2% had odds of severe falciparum malaria 12-fold higher than those of patients with parasitemias of <2% (73% vs. 19%). Patients with a history of previous clinical malaria, regardless of ethnicity, had a significantly reduced risk of WHO-defined severe falciparum malaria (odds ratio, 0.35 [95% CI, 0.15-0.80])., Conclusions: The findings of this study demonstrate that ethnicity and parasitemia are important independent risk factors for severe falciparum malaria in adults from malaria-nonendemic countries and that a history of previous clinical malaria significantly reduces the risk of WHO-defined severe falciparum malaria.

Individuals possessing red cells negative for the Duffy blood group antigen are said to possess absolute resistance to infection by the malarial parasite Plasmodium vivax. Now in this issue of Transactions, initial evidence is presented from the Brazilian Amazon to suggest that P. vivax is being transmitted amongst Duffy-negative individuals. This supports data from East Africa where the same phenomenon has been observed. Thus the emerging picture is that P. vivax in both South America and in Africa is now evolving pathways other than Duffy to enter red cells.

Background: Many adults with pulmonary tuberculosis are unable to expectorate. Gastric washing, sputum induction using nebulized hypertonic saline, and bronchoscopy with bronchoalveolar lavage have all been used to obtain specimens for diagnosis, but to our knowledge, the timing and volume of induced sputum have not been well studied, and these 3 methods have not been compared., Methods: The study recruited consecutive adult inpatients with chest radiography findings suggestive of tuberculosis who were unable to expectorate. Subjects provided 3 induced sputum samples for culture on day 1 and additional samples on days 2 and 3. In addition, gastric washing specimens were collected on days 1, 2, and 3. A proportion of subjects with negative smear results underwent bronchoalveolar lavage., Results: The study recruited 140 subjects. Among 107 subjects who provided 3 gastric washing specimens and at least 3 induced sputum specimens, 43% had cultures positive for Mycobacterium tuberculosis. Use of 3 induced sputum samples detected more cases than did use of 3 gastric washings (39% vs. 30%; P=.03). Among 79 subjects with culture results for all 5 induced sputum specimens, there was no difference in yield between samples obtained by induced sputum induction performed in a single day or that performed over 3 days (34% vs. 37%; P=.63). There was no association between sputum volume and positive culture results. No additional cases were diagnosed in the 21 patients who underwent bronchoscopy., Conclusions: Use of 3 induced sputum samples was more sensitive than use of 3 gastric washings for diagnosis of tuberculosis in patients who could not expectorate spontaneously. Use of bronchoscopy with bronchoalveolar lavage did not increase diagnostic sensitivity. Samples could be collected in 1 day, allowing for faster diagnosis, faster initiation of treatment, and shorter hospital stay.

All cases of falciparum malaria are potentially severe and life threatening, especially when managed inappropriately. A major reason for progression from mild through complicated to severe disease is missed or delayed diagnosis. Once diagnosed, the priority for treatment of complicated and severe disease is the parenteral administration of adequate, safe doses of an appropriate antimalarial, in the setting of the highest possible level of clinical care (i.e. usually an intensive care unit). Supportive management of complications such as coma, convulsions, metabolic acidosis, hypoglycaemia, fluid and electrolyte disturbances, renal failure, secondary infections, bleeding disorders and anaemia is also important. The most recent advance in antimalarial chemotherapy has been the use of artemisinin derivatives especially intravenous artesunate, which may well revolutionize the management of severe disease. Outside antimalarial therapy, mechanical ventilation and renal replacement have also played an important role in reducing mortality of this life-threatening condition.

Most cases of latent tuberculosis infection (LTBI) do not cause symptoms during the lifetime of the infected person. Longitudinal analysis of the immune response of healthy Mycobacterium tuberculosis-infected people might, therefore, give insight into the basis of protective immunity. In a longitudinal study, we documented the effect that treatment had on the T cell response to M. tuberculosis antigens in 33 healthy people with LTBI. Preventive treatment of LTBI resulted in a 1.8-fold average increase in the numbers of interferon (IFN)- gamma -producing T cells within 26 +/- 4 days (P = .006), followed by a decrease by the end of the treatment period (82 +/- 6 days; P = .004). There was no significant overall change in the T cell response to any antigen in a control group (n = 8) of patients who elected radiological follow-up. Using live M. tuberculosis strain H37Rv as a stimulant in an enzyme-linked immunospot assay in sensitized individuals, we showed that isoniazid, but not rifampin, led to an increase in the number of IFN- gamma -producing cells. These results suggest that the integrity of the bacterial cell wall is important for M. tuberculosis in avoiding immune recognition by T cells and favor a dynamic model of LTBI.

We present a case of Kikuchi's disease causing meningitis associated with fever and treated successfully with corticosteroids alone. This is considered to be rare but provides an instructive example of how the diagnosis may be confused with that of tuberculous meningitis and highlights the importance of histopathological analysis.

In a retrospective analysis, paradoxical deterioration of lymph node tuberculosis in human immunodeficiency virus-uninfected patients was common, occurring in 25 (23%) of 109 patients after treatment had been given for a median of 46 days (interquartile range, 21-139 days) and persisting for a median of 67.5 days (interquartile range, 34-111 days). We found no association between the use of steroids and the duration of reaction.

Presence of early secretory antigenic target-6 (ESAT-6)-specific, interferon- gamma -secreting T cells in blood accurately marks tuberculosis infection. In tuberculous pleural effusions from 10 patients with tuberculosis, these cells were concentrated a mean of 15-fold (standard deviation, +/-6-fold), relative to their level in peripheral blood (P=.014), and displayed rapid effector function. Such cells were absent in 8 control patients with nontuberculous pleural disease. The recruitment of ESAT-6-specific T cells to inflamed tuberculous tissue demonstrates their function in vivo and suggests a novel way to diagnose tuberculous pleuritis.

Hyponatraemia is a common finding in malaria, but rarely appears to be of clinical significance. We describe a case of acute, profound, hyponatraemia with confusion and convulsions developing in the context of seemingly uncomplicated Plasmodium falciparum malaria. We draw attention to this rarely reported and poorly documented life-threatening complication and review the limited literature on the subject.

The T cell repertoire of 59 patients with untreated tuberculosis was compared with that of 46 bacille Calmette-Guérin-vaccinated controls by assaying the proliferative responses to six permissively recognized peptides from the 16-, 19-, and 38-kDa molecules of Mycobacterium tuberculosis. A trend from higher to lower reactivity following this order: vaccinated controls > lymph node disease > localized extrapulmonary > pulmonary > pleural was seen for 4 of the peptides (P < .03). The decreased response of blood lymphocytes from patients with pleural tuberculosis was partially accounted for by sequestration of peptide-responsive cells within the pleural fluid. Chemotherapy "reversed" the depressed proliferative responses of patients with pulmonary and pleural tuberculosis depending on the peptide origin, being greatest for peptides of 16 kDa, transient for those of 19 kDa, and least for those of 38 kDa. These data demonstrate antigen specificity in the decreased responsiveness of patients with tuberculosis.

The T cell response to a mixture of eight peptides derived from sequences of the Mycobacterium tuberculosis 16-, 19- and 38-kD antigens (MTBmix-8) has been studied. The peptides were selected on the basis of complementary binding to nine HLA-DR molecules (HLA-DR1 to DR9). MTBmix-8 at 6.25 and 50 micrograms/ml gave rise to significant stimulation (P < 0.05) of peripheral blood mononuclear cells (PBMC) from healthy tuberculin-positive and both untreated and treated diseased subjects, but not in any of a control group of healthy tuberculin-negative subjects. MTB-mix-8 stimulated proliferation of PBMC from healthy tuberculin-positive individuals at lower concentrations than the individual component peptides. However, the maximal stimulation achieved was only slightly higher than that achieved with individual peptides. MTBmix-8 also stimulated the production of interferon-gamma (IFN-gamma) in vitro. Using the mean +/- 2 s.d. of the values for IFN-gamma production in the tuberculin-negative population as a cut-off, MTBmix-8 at 6.25 micrograms/ml was able to detect infection with a sensitivity of 100% in untreated patients, 87% in treated patients, and 82% in tuberculin-positive controls. The corresponding figures for the most potent single peptide (16p91-110) were: 66% in untreated patients, 71% in treated patients and only 42% in controls. Thus, using the IFN-gamma-based assay, which has the additional advantages of speed and does not require radioactivity, the mixture of peptides is more sensitive than single peptides in diagnosing infection.

A rapid, simple diagnostic polymerase chain reaction (PCR) method for the diagnosis of dengue fever was developed using a pair of consensus oligonucleotide primers and validated with laboratory-derived strains of dengue serotypes 1-4 and other common flaviviruses. A cluster of 13 patients with clinical dengue fever admitted to a single infectious diseases unit over a period of 3 months allowed evaluation of this technology. The PCR was positive in all 11 acute dengue cases and negative in 2 convalescent cases and 10 febrile patients recently returned from the tropics in whom an alternative diagnosis was established. In some of the acute cases, viraemia was detected before the development of a diagnostic antibody response (indirect immunoglobulin (Ig) G enzyme-linked immunosorbent assay (ELISA) and capture IgM ELISA). In patients from whom sequential sera were taken, defervescence and recovery from thrombocytopenia coincided with the disappearance of dengue ribonucleic acid from the blood. Nucleotide sequencing of the PCR products was undertaken in 2 cases (from India and Guyana) and the results showed a close match with previously reported serotype 2 sequencies, suggesting a potential for use of this region of the genome in epidemiological studies.

The 16-kD protein constituent of the Mycobacterium tuberculosis complex has been known mainly for its prominent serological immunogenicity and species specificity in tuberculous infection. In this study, we evaluated the T cell immune repertoire in 27 sensitized healthy subjects and 46 patients with active tuberculosis using 14 overlapping 20mer peptides spanning the entire sequence of this protein. Four of the tested peptides individually stimulated proliferation of blood mononuclear cells from more than 50% of healthy controls. Tuberculosis patients reacted to a narrower peptide range and with a 17-27% lower rate of responses to the four most immunogenic peptides, but these differences do not distinguish in any simple way between the T cell repertoire of patients and sensitized healthy subjects. The most immunogenic peptide (91-110) was recognized by 67% of healthy subjects and by 50% of tuberculosis patients. Importantly, several non-responders to this peptide were stimulated with the other three most permissive peptides with sequences of 111-130, 71-91 and 21-40, resulting in an overall response rate to at least one of these four peptides of 93% in healthy controls and 74% in tuberculosis patients. In view of this additive effect between the most immunogenic peptides, their combined use may achieve sufficient sensitivity in a test aimed at the specific discrimination between infected and non-infected healthy subjects. The major interest in testing with these peptides rests in their species specificity, which is not achieved using purified protein derivative (PPD).

Toxic shock-like syndrome is a serious complication of invasive streptococcal disease. The syndrome is believed to be the consequence of exposure to exotoxins produced by the infecting organisms which behave as superantigens. We describe two patients who fulfilled clinical criteria for this syndrome, one of whom died. Streptococci isolated from both patients were found to produce a mitogen specific for the V beta 2+ T lymphocyte subset in vitro, which had the characteristics of a superantigen. The phenotype and function of lymphocytes collected from both patients during the acute phase of their illness demonstrated a marked reduction in circulating CD4+ ('helper') and CD45RA+ ('naive') T lymphocytes expressing the V beta 2 chain, and an increase of those expressing CD8, CD45RO and the V beta 2 chain. This effect resolved within 4 weeks in the patient who survived. Proliferation assays demonstrated no T cell anergy in either patient. Stimulation of lymphocytes by superantigen in these clinical situations does not appear to cause permanent deletion of T cell subsets, as has been observed in animal models.

Young African children with severe malaria are given quinine using a regimen designed for Thai adults. We measured quinine in the blood, plasma and plasma water of young children in Kenya after rapid intravenous and intramuscular dosing, and calculated the therapeutic range of unbound quinine. The peak plasma quinine concentration after rapid intravenous dosing was 12.3 +/- 3.7 mg/L (mean +/- SD), 43% higher than in adults given the same regimen previously; this was due to a smaller apparent volume of distribution in the children. The therapeutic range of unbound quinine was calculated as 0.2-2.0 mg/L. Simulations of unbound quinine were made for the standard quinine regimen: unbound drug concentrations rose above the therapeutic range after each dose. The possible risks of quinine-induced visual impairment are discussed. Alternative, lower dose regimens for young African children with severe malaria are described.

Disease progression, support required, prognostic indicators and survival in hospital and after discharge were studied in 53 patients with community acquired infections who required admission to the intensive care unit from the Department of Infectious Diseases between January, 1985 and August, 1991. The median age was 37 years and over two-thirds of patients were previously fully fit; 38 per cent of patients required intensive care within 6 hours of admission with rapidly progressive disease. Both APACHE II scores and number of organ systems failed were good indicators of prognosis: mortality was 85 per cent in those with three or more organ failures and 86 per cent in those with APACHE II scores of > or = 25. No deaths were observed in those with scores of < 10. Some organ failures (cardiovascular, renal and respiratory) occurred more frequently in those who died. Mechanical ventilation was required by 60 per cent of patients, inotropic drugs by 42 per cent and renal dialysis by 17 per cent. Mortality in hospital was 25 per cent with no further deaths at 6 months to 2 years. As a group these patients were young and previously fit. Deterioration was rapid, necessitating admission to the intensive care unit at short notice. Our results highlight the importance of having intensive care facilities in close proximity to infectious disease units. In contrast to many other groups of patients admitted to the intensive care unit, the overall outlook for patients with community acquired life-threatening infections is good, and long-term monitoring suggests that these patients remain well once recovery has occurred.

The mechanism whereby heterozygous carriers of the sickle cell gene are protected against fatal malarial infections due to Plasmodium falciparum has been examined in a short term in vitro cultivation system. The results have shown that both parasite invasion of red cells and parasite growth within red cells containing sickle haemoglobin (Hb-S) is restricted, but only under conditions of low (5%) oxygen tensions. To bring this about, the cells containing Hb-S need not sickle. Furthermore the growth retardation observed in the presence of Hb-S was also found to apply to the mature forms of the parasite. These findings offer a plausible mechanism for the protection of sickle heterozygotes against falciparum malaria.