A case series describing common radiographic and pathologic patterns of hard metal pneumoconiosis.

INTRODUCTION: Hard metal pneumoconiosis is a rare but serious disease of the lungs associated with inhalational exposure to tungsten or cobalt dust. Little is known about the radiologic and pathologic characteristics of this disease and the efficacy of treating with immunosuppression. OBJECTIVE: We describe the largest cohort of patients with hard metal pneumoconiosis in the literature, including radiographic and pathologic patterns as well as treatment options. METHODS: We retrospectively identified patients from the University of Pittsburgh pathology registry between the years of 1985 and 2016. Experts in chest radiology and pulmonary pathology reviewed the cases for radiologic and pathologic patterns. RESULTS: We identified 23 patients with a pathologic pattern of hard metal pneumoconiosis. The most common radiographic findings were ground glass opacities (93%) and small nodules (64%). Of 20 surgical biopsies, 17 (85%) showed features of giant cell interstitial pneumonia. Most patients received systemic corticosteroids and/or steroid-sparing immunosuppression. CONCLUSIONS: Hard metal pneumoconiosis is characterized predominately by radiographic ground glass opacities and giant cell interstitial pneumonia on histopathology. Systemic corticosteroids and steroid-sparing immunosuppression are common treatment options.

Antifibrotic therapy for the treatment of pulmonary fibrosis.

Fibroproliferative lung disease is prevalent and associated with high mortality. The pathogenesis of fibrotic lung disease involves inflammation, mesenchymal cell proliferation, and deposition of interstitial matrix components, such as collagen and fibronectin. Corticosteroids and other immunosuppressive medications have been routinely employed, but have demonstrated only marginal efficacy. Even though this information has been known for some time, the optimal medical regimen for treating pulmonary fibrosis remains largely undefined. This article addresses the rationale for, and efficacy of, antifibrotic regimens used to treat humans with fibrotic lung diseases.

Effects of cigarette smoke in mice with different levels of alpha(1)-proteinase inhibitor and sensitivity to oxidants.

The role of strain difference in the response to cigarette smoke was investigated in mice. Mice of the strains DBA/2 and C57BL/6J responded to acute cigarette smoke with a decrease of the antioxidant defenses of their bronchoalveolar lavage (BAL) fluids. On the other hand, under these conditions ICR mice increased their BAL antioxidant defenses. Mice of these three strains were then exposed to cigarette smoke (three cigarettes/d, 5 d/wk) for 7 mo. Lung elastin content was significantly decreased in C57BL/6J and DBA/2 but not in ICR mice. Also, emphysema, assessed morphometrically using three methods, was present in C57BL/6J and DBA/2 but not in ICR mice. In an additional study pallid mice, with a severe serum alpha(1)-proteinase inhibitor (alpha(1)-PI) deficiency and that develop spontaneous emphysema, were exposed to cigarette smoke for 4 mo. This resulted in an acceleration of the development of the spontaneous emphysema assessed with morphometrical and biochemical (lung elastin content) methods. All these results indicate that sensitivity to the effects of cigarette smoke is strain-dependent and cigarette smoke accelerates the effects of alpha(1)-PI deficiency.

Role of LPS and receptor subtypes in the uptake of TNF by the murine lung.

Tumor necrosis factor alpha (TNF) is an important mediator in lung injury. The kinetics of TNF uptake by the lung are not completely understood. In this study, we evaluated the role that lipopolysaccharide (LPS) and the two types of TNF receptor (p55 and p75) play in the uptake of circulating murine TNF by the murine lung. TNF radioactively labeled with 125I (I-mTNF) was administered intravenously (2 x 10(6) cpm/mouse) to mice with both receptors (wild-type) or to mice missing one (p55-/- or p75-/-) or both (p55-/- and p75-/-) TNF receptors. Blood to lung non-reversible sequestration (Ki) and reversible uptake (Vi) were measured with multiple-time regression analysis. Uptake by lung of I-mTNF in wild-type mice had reversible and non-reversible components. This uptake was decreased by intratracheal, but not by intravenous, LPS, suggesting modulation by local, rather than systemic, inflammation. The p75-/- deficient mice retained the Ki (saturable, non-reversible) component of TNF uptake, whereas p55-/- deficient mice retained the Vi (saturable, reversible) component of TNF uptake. Both Ki and Vi components of TNF uptake were absent in the lungs of p55-/- p75-/- deficient mice. These studies show that local inflammation inhibits the uptake of circulating I-mTNF by lung and that uptake consists of two distinguishable compartments: reversible uptake mediated by the p75 receptor and non-reversible sequestration mediated by the p55 receptor.

Effect of prenatal dexamethasone on rat renal development.

BACKGROUND: Prenatal insults can program the developing fetus to develop diseases that manifest in later life. Dexamethasone is often administered to the developing fetus to accelerate pulmonary development. The purpose of the present study was to determine whether prenatal dexamethasone adversely affects renal development and predisposes rats to develop renal disease and hypertension in later life. METHODS: Pregnant rats were given either vehicle or two daily intraperitoneal injections of dexamethasone (0.2 mg/kg body weight) on gestational days: 11 and 12, 13 and 14, 15 and 16, 17 and 18, 19 and 20, or 20 and 21. Tail cuff blood pressure, glomerular number, and inulin clearance were measured in control and prenatal dexamethasone-treated rats when the rats were 60 to 90 days of age. RESULTS: Prenatal dexamethasone did not affect the length of gestation, the number of animals per litter, or the total body weight or kidney weight measured at one day of age. Offspring of rats administered dexamethasone on days 15 and 16 gestation had a 30% reduction in glomerular number compared with control at 60 to 70 days of age (24,236 +/- 441 vs. 30,453 +/- 579, P < 0.01). Rats receiving prenatal dexamethasone on days 17 and 18 had an approximate 20% reduction in glomeruli compared with control (P < 0.01). Offspring of rats receiving dexamethasone on days 15 and 16 gestation had systolic blood pressures at 60 to 90 days of age that were higher than any other group (P < 0.05). The glomerular filtration rate was comparable in all of the groups. CONCLUSIONS: This study shows that two daily doses of prenatal dexamethasone (0.2 mg/kg body weight) in rats do not produce intrauterine growth retardation. Adult offspring of rats that received prenatal dexamethasone during specific times of gestation have a reduced number of nephrons and hypertension.

Tumor necrosis factor receptor deficiency alters matrix metalloproteinase 13/tissue inhibitor of metalloproteinase 1 expression in murine silicosis.

Murine exposure to silica is associated with enhanced tumor necrosis factor alpha (TNF-alpha) expression and matrix deposition. The regulation of TNF is mediated through TNF receptor (TNFR) activation of transcription factors. In the present work we have studied the importance of the individual TNFR in silica-induced lung inflammation and matrix deposition in mice. We studied RNA expression of TNF, alpha1(I) collagen, interstitial collagenase (MMP-13), and its inhibitor (TIMP-1) in the lungs of silica-treated mice. Furthermore, we correlated MMP-13/TIMP-1 RNA abundance with activation of the transcription factors AP-1 and NF-kappaB in the lungs of C57BL/6 mice, and of mice deficient in one of the two types of TNFR (p55(-/-) or p75(-/-)), exposed to silica (0.2 g/kg) or saline by intratracheal instillation. Animals were killed 28 d after exposure and lung hydroxyproline (HP), TNF, alpha1(I) collagen, MMP-13, and TIMP-1 RNA abundance was measured. AP-1 and NF-kappaB activation was studied by gel-shift assays. Compared with C57BL/6 mice, p55(-/-) and p75(-/-) mice significantly (*p < 0.05) decreased lung HP accumulation in response to silica. All murine strains enhanced TNF and alpha1(I) collagen mRNA in response to silica. Enhanced (p < 0.05) MMP-13 RNA expression was also observed in all murine strains in response to silica. Enhanced (p < 0.05) TIMP-1 RNA expression was observed in C57BL/6 mice, but not in p55(-/-) or p75(-/-) mice, in response to silica. NF-kappaB activation was observed in all murine strains, whereas AP-1 activation was observed only in C57BL/6 mice after silica treatment. These data suggest that TNFR deletion modifies MMP-13/ TIMP-1 expression in favor of matrix degradation.

Formation of a novel trinuclear spirostannoxane tin(IV) compound. Crystal and molecular structure of [Sn(nBu)(Cl)[(OCH2CH2S)2Sn(nBu)]2] and the stannolane [(nBu)Sn(SCH2CH2O)SCH2CH2OH].

The reaction of nBuSnCl3 and the sodium salt of 2-mercaptoethanol (1:1) in ethanol gave the compound Sn(nBu)(Cl)[(OCH2CH2S)2Sn(nBu)]2 (1). [(nBu)Sn(SCH2CH2O)SCH2CH2OH] (2) was initially isolated from the reaction of 1 with nBuMgCl as a rearrangement product but was also synthesized from nBuSn(O)OH and two molar equivalents of 2-mercaptoethanol. Both compounds were characterized by means of IR, 119Sn, 13C, and 1H NMR, FAB mass spectroscopy, and elemental analyses. The structures were determined by single-crystal X-ray diffraction. 1 crystallizes in the monoclinic Cc space group (a = 18.492(3) A, b = 17.329(2) A, c = 10.787(1) A, beta = 111.88(1) degrees, Z = 4), while 2 crystallizes in the orthorhombic Pbca space group (a = 14.458(2) A, b = 10.393(1) A, c = 16.479(2) A, Z = 8). 1 is a trimetallic Tin(IV) compound in which the central atom is in 6-fold coordination, while the two remaining tin atoms show 5-fold coordination. Both pentacoordinated tin atoms are bonded to a butyl group and to the oxygen and the sulfur atoms from two [OCH2CH2S]2- ligands forming two stannolanes, which are fused with the hexacoordinated tin atom forming a distannoxane system. This arrangement is quite different from previous ladder or staircase structures. NMR data point to maintenance of this structure in solution. 2 consists of [(nBu)Sn(SCH2CH2O)(SCH2CH2OH)] units, which are associated via intermolecular Sn-O interactions building up a dimer. The tin atom forms two "stannolane" units by interaction with [OCH2CH2S]2- and [HOCH2CH2S]- ligands.

Exacerbation of bleomycin-induced lung injury in mice by amifostine.

Bleomycin (BLM) induces lung injury and fibrosis in the murine lung and enhances tumor necrosis factor (TNF)-alpha and collagen mRNA expression in the murine lung. Amifostine is a cytoprotective agent that protects normal tissues from the cytotoxic effects of chemo- and radiation therapy. We investigated the effect of amifostine in BLM-induced lung injury in mice. Mice received intraperitoneal amifostine (200 mg/kg) 30 min before and/or 1, 3, and 7 days after an intratracheal injection of saline or BLM (4 U/kg). The animals were killed 14 days after BLM exposure, and their lungs were studied for TNF-alpha and collagen mRNA expression, hydroxyproline content, and histopathology. Light microscopy demonstrated that amifostine exacerbated the BLM-induced lung injury in mice. Increased TNF-alpha mRNA expression as a result of BLM exposure was not modulated by amifostine treatment. In contrast, amifostine treatment enhanced the BLM-induced expression of alpha(1)(I) procollagen mRNA in the lung. Similarly, mice treated with amifostine before BLM exposure accumulated significantly higher amounts of hydroxyproline (111 +/- 5 microg/lung) than BLM-treated animals (90 +/- 6 microg/lung). These data suggest that amifostine treatment exacerbates BLM-induced lung injury in mice.

Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo. Effect on agonist-induced and flow-mediated vascular responses.

The effects of transfer of the endothelial nitric oxide synthase (eNOS) gene to the lung were studied in mice. After intratracheal administration of AdCMVbetagal, expression of the beta-galactosidase reporter gene was detected in pulmonary airway cells, in alveolar cells, and in small pulmonary arteries. Gene expression with AdCMVbetagal peaked 1 day after administration and decayed over a 7- to 14-day period, whereas gene expression after AdRSVbetagal transfection peaked on day 5 and was sustained over a 21- to 28-day period. One day after administration of AdCMVeNOS, eNOS protein levels were increased, and there was a small reduction in mean pulmonary arterial pressure and pulmonary vascular resistance. The pressure-flow relationship in the pulmonary vascular bed was shifted to the right in animals transfected with eNOS, and pulmonary vasodepressor responses to bradykinin and the type V cGMP-selective phosphodiesterase inhibitor zaprinast were enhanced, whereas systemic responses were not altered. Pulmonary vasopressor responses to endothelin-1 (ET-1), angiotensin II, and ventilatory hypoxia were reduced significantly in animals transfected with the eNOS gene, whereas pressor responses to norepinephrine and U46619 were not changed. Systemic pressor responses to ET-1 and angiotensin II were similar in eNOS-transfected mice and in control mice. Intratracheal administration of AdRSVeNOS attenuated the increase in pulmonary arterial pressure in mice exposed to the fibrogenic anticancer agent bleomycin. These data suggest that transfer of the eNOS gene in vivo can selectively reduce pulmonary vascular resistance and pulmonary pressor responses to ET-1, angiotensin II, and hypoxia; enhance pulmonary depressor responses; and attenuate pulmonary hypertension induced by bleomycin. Moreover, these data suggest that in vivo gene transfer may be a useful therapeutic intervention for the treatment of pulmonary hypertensive disorders.

Upregulation of the p75 but not the p55 TNF-alpha receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice.

We have investigated a potential role for tumor necrosis factor (TNF)-alpha and its two receptors (p55 and p75) in lung injury. We used several varieties of mice exposed endotracheally to two fibrogenic agents, silica (0.2 g/kg) and bleomycin (4 U/kg). The lungs were analyzed at 14 and 28 d after exposure to bleomycin or silica, respectively, for TNF and TNF receptor (TNFR) messenger RNA (mRNA), hydroxyproline content, and histopathology. Silica induced increased (over saline-treated animals) expression of TNF mRNA in double TNFR knockout (Ko), C57BL/6, BALB/c, and 129/J mice. In contrast, bleomycin increased expression in all but BALB/c mice, which are resistant to the fibrogenic effects of this drug. mRNA expression of both receptors was constitutively expressed in all of the normal murine strains. Silica upregulated expression of the p75 receptor, but not the p55 receptor, in the C57BL/6, BALB/c, and 129/J mice. In comparison, bleomycin had little effect on either receptor in the bleomycin-resistant BALB/c mice. Hydroxyproline content of the lungs after treatment followed this same pattern, with significant increases caused by silica in the C57BL/6, BALB/c, and 129/J mice, whereas bleomycin caused no apparent increases in the BALB/c mice. Even though silica and bleomycin induced increases in TNF in the TNFR Ko mice, the mice were protected from the fibrogenic effects of these agents. This study supports the concept that TNF is a central mediator of interstitial pulmonary fibrosis.

Expression of TNF and the necessity of TNF receptors in bleomycin-induced lung injury in mice.

Bleomycin (BLM) induction of lung fibrosis in mice is an established model to study the mechanism of pulmonary fibrosis. Cytokine secretion has been implicated as a fundamental component of the lung fibrotic process observed in response to BLM. Among the cytokines implicated in lung fibrosis, Tumor necrosis factor (TNF) alpha has been considered to play a fundamental role. In the present study, we characterized the cellular sources of TNF during BLM-induced lung injury and examined the importance of TNF receptors in this process. To characterize the expression of TNF, we utilized two strains of mice, one sensitive (C57BL/6) and one resistant (BALB/c) to BLM-induced lung injury. Mice received BLM (120 mg/kg total) or saline, as control, by multiple subcutaneous injections. BLM induced the development of inflammation in subpleural areas only in the lungs of BLM-sensitive mice. These subpleural areas were characterized by infiltration of CD68-positive macrophages and increased collagen deposition. BLM enhanced the expression of TNF mRNA in BLM-sensitive, but not in BLM-resistant, mice. In situ hybridization studies localized the expression of TNF in the areas of BLM-induced inflammation in 6% and 27% of macrophages at 14 and 21 days post BLM treatment. In addition to TNF, BLM exposure resulted in the upregulated expression of transforming growth factor (TGF)-beta 1, but not interleukin (IL)-1, mRNA in the lungs of both murine strains at 14 and 21 days. This upregulated expression of TGF-beta 1 mRNA was greater in the lungs of BLM-sensitive mice. In separate experiments, double TNF receptor knockout mice were exposed to BLM. These animals demonstrated an increased expression of TNF, but not TGF-beta 1, mRNA in response to BLM and did not exhibit histologic evidence of lung injury following BLM exposure. In summary, the upregulation of TNF mRNA in macrophages correlated with the appearance of inflammation following BLM exposure and was limited to the BLM-sensitive strain. Furthermore, in addition to the release of the TNF ligand, it appears that the presence of TNF receptors is necessary for the development of BLM-induced lung injury, and signaling through these receptors may contribute to the regulation of the TGF-beta 1 mRNA expression observed in response to bleomycin. These results provide further support for a role of macrophages and TNF in the induction of lung inflammation.

Alveolar macrophage apoptosis and TNF-alpha, but not p53, expression correlate with murine response to bleomycin.

Apoptosis is considered to be a protective mechanism that limits lung injury. However, apoptosis might contribute to the inflammatory burden present in the injured lung. The exposure of mice to bleomycin (BLM) is a well-established model for the study of lung injury. BLM exposure induces DNA damage and enhances tumor necrosis factor (TNF)-alpha expression in the lung. To evaluate the importance of alveolar macrophage (AM) apoptosis in the pathogenesis of lung injury, we exposed BLM-sensitive (C57BL/6) and BLM-resistant (BALB/c) mice to BLM (120 mg/kg) and studied the induction of apoptosis [by light-microscopy changes (2, 8, 12, 24, 48, and 72 h) and annexin V uptake by flow cytometry (24 h)], the secretion of TNF-alpha (measured by ELISA), and the expression of p53 (by immunoblotting) in AM retrieved from these mice. BLM, but not vehicle, induced apoptosis in AM from both murine strains. The numbers of apoptotic AM were significantly greater (P < 0.001) in C57BL/6 mice (52.9%) compared with BALB/c mice (40.8%) as demonstrated by annexin V uptake. BLM induction of apoptosis in AM was preceded by an increased secretion of TNF-alpha in C57BL/6 but not in BALB/c mice. Furthermore, double TNF-alpha receptor-deficient mice, developed on a C57BL/6 background, demonstrated significantly (P < 0.001) lower numbers of apoptotic AM compared with C57BL/6 and BALB/c mice. BLM also enhanced p53 expression in AM from both murine strains. However, p53-deficient mice developed BLM-induced lung injury, exhibited similar lung cell proliferation (measured as proliferating cell nuclear antigen immunostaining), and accumulated similar amounts of lung hydroxyproline (65 +/- 6.9 microgram/lung) as did C57BL/6 (62 +/- 6.5 microgram/lung) mice. Therefore, AM apoptosis is occurring during BLM-induced lung injury in a manner that correlates with murine strain sensitivity to BLM. Furthermore, TNF-alpha secretion rather than p53 expression contributes to the difference in murine strain response to BLM.tumor necrosis factor; strain susceptibility

Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis.

Connective tissue growth factor (CTGF) is a newly described 38-kDa peptide mitogen for fibroblasts and a promoter of connective tissue deposition in the skin. The CTGF gene promotor contains a transforming growth factor-beta1 (TGF-beta1) response element. Because TGF-beta1 expression is upregulated in several models of fibroproliferative lung disease, we asked whether CTGF is also upregulated in a murine lung fibrosis model and whether CTGF could mediate some of the fibrogenic effects associated with TGF-beta1. A portion of the rat CTGF gene was cloned and used to show that primary isolates of both murine and human lung fibroblasts express CTGF mRNA in vitro. There was a greater than twofold increase in CTGF expression in both human and murine lung fibroblasts 2, 4, and 24 h after the addition of TGF-beta1 in vitro. A bleomycin-sensitive mouse strain (C57BL/6) and a bleomycin-resistant mouse strain (BALB/c) were given bleomycin, a known lung fibrogenic agent. CTGF mRNA expression was upregulated in the sensitive, but not in the resistant, mouse strain after administration of bleomycin. In vivo differences in the CTGF expression between the two mouse strains were not due to an inherent inability of BALB/c lung fibroblasts to respond to TGF-beta1 because fibroblasts from untreated BALB/c mouse lung upregulated their CTGF message when treated with TGF-beta1 in vitro. These data demonstrate that CTGF is expressed in lung fibroblasts and may play a role in the pathogenesis of lung fibrosis.

Pulmonary involvement in rheumatoid arthritis.

Pulmonary involvement is one of the extra-articular manifestations of rheumatoid arthritis (RA) and includes pleurisy, parenchymal nodules, interstitial involvement, and airway disease. Rheumatoid pulmonary vasculitis is rare. Pulmonary disease also may be observed as a toxic event consequent to treatment for RA. Although RA is more common in women, rheumatoid lung disease occurs more frequently in men who have long-standing rheumatoid disease, positive rheumatoid factor and subcutaneous nodules. Pleural involvement, usually asymptomatic, is the most common manifestation of lung disease in RA and may occur concurrently with pulmonary nodulosis or interstitial disease. The clinical features and course of pulmonary fibrosis in RA are similar to those of idiopathic pulmonary fibrosis. Bronchiolitis obliterans organizing pneumonia (BOOP), which has been recently described in RA patients, has nonspecific clinical features. The histological patterns correspond to proliferative bronchiolitis in the airway and organizing pneumonia in the alveoli. Obstructive lung disease in RA includes obliterative bronchiolitis (OB) and bronchiectasis. OB is an acute illness characterized histologically by a constrictive bronchiolitis. It may be idiopathic or induced by D-penicillamine or intramuscular gold compounds. Methotrexate (MTX)-pneumonitis is an uncommon complication of MTX treatment. Its clinical presentation is not specific, and diagnosis must be made after exclusion of other causes of pulmonary diseases. It is uncertain if preexisting lung disease predisposes RA patients to MTX-pneumonitis. Treatment of lung disease in RA is empirical. Corticosteroids are usually administered and immunosuppressive drugs are often added when pulmonary disease progresses and/or steroid side-effects appear.

His64(E7)-->Tyr apomyoglobin as a reagent for measuring rates of hemin dissociation.

To develop an assay for hemin dissociation, His64(E7) was replaced by Tyr in sperm whale myoglobin producing a holoprotein with a distinct green color due to an intense absorption band at 600 nm. Val68(E11) was replaced by Phe in the same protein to increase its stability. When excess Tyr64-Val68 apoglobin is mixed with either metmyoglobin or methemoglobin, the solution turns from brown to green, and the absorbance changes can be used to measure complete time courses for hemin dissociation from either holoprotein. This assay has been used to measure rates of hemin dissociation from native metmyoglobin, four myoglobin mutants (Ala64(E7), Ala68(E11), Phe68(E11), and Glu45(CD3)), native methemoglobin, valence hybrid hemoglobins, and two mutant hemoglobins ((alpha(Gly-E7)beta(native))2, and (alpha(native)beta(Gly-E7))2). Two kinetic phases were observed for hemin dissociation from native human hemoglobin at pH 7.0 and 37 degrees C. Valence and mutant hybrid hemoglobins were used to assign the faster phase (k = 7.8 +/- 2.0 h-1) to hemin dissociation from ferric beta subunits and the slower (k = 0.6 +/- 0.15 h-1) to dissociation from alpha subunits. The corresponding rate for wild-type metmyoglobin is 0.007 +/- 0.004 h-1.

[Lymphocyte transformation in allergy to penicillin]. / Transformación linfocitaria en alergia a la penicilina.

Thirty patients both sexes with ages between 1-52 years old, thinking that they are allergic to penicillin, were studied because they were found to have some clinic symptoms immediately after the administration of penicillin procain I.M. (intramuscle) such as urticaria, angioedema, anaphylactic shock and Stevens-Johnson syndrome. In order to confirm or to discard this asseveration an in-vitro lymphocyte transformation test was realized, with the venous peripherical blood of each patient, using the greater determinative of penicillin: the peniciloil. The results obtained were twelve negatives, twelve on doubt and six positives. These results show that the in-vitro lymphocyte transformation test may be useful to decide, when a patient could be considered allergic or not to penicillin.

[Immunological status of patients with amebic hepatic abscess]. / Estado inmunológico en pacientes con absceso hepático amibiano

The authors studied 10 cases of amoebic hepatic abscess documented by clinical evidence and confirmed by laboratory tests, liver scan and a good response to treatment. The immunological state of the patients was determined by protein electrophoresis, immunoelectrophoresis, counter-immunoelectrophoresis, radial immunodiffusion and roset formation for T and B lymphocytes. It is concluded that the alterations of cellular and humoral immunity is evident in cases of amoebic hepatic abscess; this alterations are more clear in the acute form of the illness and the immunological deficiency is more significant in the celular immunity.