Acquired alpha 1-antitrypsin deficiency in tropical pulmonary eosinophilia.

Background & objectives: Observation of an increased frequency of an intermediate deficiency of serum alpha1-antitrypsin (α1-AT) in patients with Tropical Pulmonary Eosinophilia (TPE) was earlier reported. Though the possibility of existence of an acquired deficiency was suggested, without phenotyping a hereditary α1-AT deficiency in TPE could not totally be ruled out. In this study, we have done Pi (Protease inhibitor) phenotyping to investigate the possibility of association of any heterozygous (or homozygous) α1-AT deficiency in patients with TPE. Methods: Serum a1antitrypsin (α1-AT) was measured in 103 patients (Group A) with TPE, 99 patients with pulmonary eosinophilia who had associated intestinal worm infestation (Group B) and 43 healthy volunteers who served as controls. In 19 α1-AT deficient patients (9 of Group A and 10 of Group B), α1-AT level was measured before and after treatment. In 58 patients with TPE and in 5 controls, phenotyping was done. Results: Fifteen patients of Group A and 16 from Group B showed intermediate α1-AT deficiency (150 mg % or less. None of the control subjects had α1-AT deficiency (<200 mg%). After treatment with DEC and/or deworming, in 19 patients there was a significant (P < 0.001) rise in α1-AT levels. Results of phenotyping showed that all had M1 or M2 allele and none had S or Z variant (either homozygous or heterozygous) thus ruling out any underlying genetic cause for the observed α1-AT deficiency. Interpretation & conclusions: The observed α1-AT deficiency may be due to the chronic inflammation in TPE and associated oxidative stress. However, in such α1-AT deficient patients with TPE and those with worm infested pulmonary eosinophilia, faecal α1-AT concentration and faecal α1-AT clearance should be routinely estimated to rule out the possibility of any intestinal protein loss.

Serum C3d levels in tropical pulmonary eosinophilia.

Background & objectives: Results of earlier studies to evaluate the possible role of complement system in tropical pulmonary eosinophilia (TPE) using classical methods like serum haemolyte component CH50, C3 and C4 levels were inconclusive. In this study we determined levels of serum C3d which is a catabolic fragment of C3, to find out any direct evidence of activation of the complement system in TPE. Methods: The study population consisted of 3 groups. Group A consisted of 37 patients with well characterized TPE. In group B, 26 patients with pulmonary eosinophilia had similar respiratory and haemotological features as in Group A but had associated worm infestation in stool. The control group consisted of 39 healthy volunteers. Serum C3d levels were determined by sandwich ELISA technique. Results: The serum C3d levels in TPE patients were not significantly different from those of the patients of group B or the normal controls. Interpretation & conclusions: Absence of significant change in serum C3d goes against the possibility of complement activation in TPE. Results of our study suggest that complement system is unlikely to play a pivotal role in pathogenesis of TPE.

Pharmacokinetics of lamivudine & stavudine in generic fixed-dose combinations in HIV-1 infected adults in India.

Background & objectives: Antiretroviral drug concentrations are important determinants of clinical response to a drug accounting for both toxicity and efficacy. Several factors such as age, ethnicity, body weight and patients’ immune status may influence antiretroviral drug concentrations. The aim of the study was to determine the influence of immunological status, sex and body mass index on the steady state pharmacokinetics of lamivudine (3TC) and stavudine (d4T) in HIV-infected adults, who were undergoing treatment with generic fixed dose combinations (FDC) of these drugs in India. Methods: Twenty seven HIV-1 infected patients receiving antiretroviral treatment (ART) for at least two weeks at the Government ART clinic at Tambaram, Chennai, took part in the study. Serial blood samples were collected predosing and at different time points after drug administration. Plasma 3TC and d4T levels were estimated by HPLC. Results: The patients’ immune status, sex or body mass index had no impact on the pharmacokinetics of 3TC. In the case of d4T, peak concentration was significantly lower in patients with CD4 cell counts < 200 cells/μl than those with ≥ 200 cells/ μl (P < 0.05), but were within the therapeutic range. The mean CD4 cell counts increased from 101 cells/μl at initiation of ART to 366 cells/μl at 12 months of treatment. Interpretation & conclusions: Blood levels of 3TC and d4T drugs that are part of generic FDCs commonly used by HIV-infected individuals in India were within the therapeutic range and not influenced by nutritional or immune status. There was a significant improvement in CD4 cell counts over 12 months of treatment. Indian generic FDCs manufactured and used widely in the developing world provide effective concentrations of antiretroviral drugs.

Incomplete immunological recovery following anti-tuberculosis.

Background & objectives: Mycobacterium tuberculosis infection has been shown to result in increased HIV replication and disease progression in HIV-infected individuals through increased immune activation. The objective of this study was to correlate plasma levels of immune activation markers with the presence of tuberculosis (TB) in HIV-infected and uninfected individuals, and to study the changes following anti-tuberculosis treatment. Methods: Plasma markers of immune activation - neopterin, beta-2-microglobulin (β2M) and soluble tumour necrosis factor alpha receptor type I (sTNFα-RI) were measured by ELISA in 42 HIV positive TB patients (HIV+TB+) undergoing a six-month course of TB chemotherapy. Thirty seven HIV+ persons without active TB, 38 TB patients without HIV infection, and 62 healthy volunteers served as controls. Results: Plasma levels of all three markers were elevated in HIV+ individuals, more so in those with active TB. When HIV+ individuals were further categorized based on CD4+ T cell counts, HIV+TB+ patients with CD4+ T cells counts < 200 cells/μl were found to have the highest levels at baseline with a steep fall in neopterin and sTNFα-RI during treatment, but in most instances the levels did not drop to normal. β2M levels remained persistently high despite completing TB treatment. Interpretation & conclusions: The fi ndings of the study suggest that both HIV and TB act synergistically to activate the host immune system. Although ATT was effective in clearing M. tuberculosis infection, a high proportion of HIV+ TB patients continued to have levels well above the normal range, indicating that underlying immune activation persists despite TB treatment. None of the markers were specific enough to be used to assess cure of TB.