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Anti-infective strategies in neutropenia.

Anti-infective strategies in febrile neutropenic patients have evolved continuously over the past decade. The changing spectrum of not only the infecting organisms but also of the underlying disease have necessitated different approaches. While the duration and degree of neutropenia have remained the most important risk factors for the development of invasive infections, other factors such as the presence of catheters, cytotoxic chemotherapy, mucositis, infection history, microbial colonisation and the concomitant immune dysfunction, also play a major role in the design of the anti-infective strategy. Individualisation of treatment strategy and the need for flexibility in response to local microbial ecology have also become key concepts. Controversy still surrounds the optimal prophylactic and empirical therapeutic regimens. Selective suppression of the endogenous microbial flora, particularly of the alimentary tract and other mucosal surfaces is recommended for high risk patients, such as those with anticipated profound and prolonged neutropenia, severe post chemotherapy mucositis and the presence of long-term intravenous catheters. For all other risk categories, cost benefit ratios must be carefully weighed against potential clinical benefit. Empirical monotherapy with broad-spectrum cephalosporins or a carbapenem is accepted as a cost-effective and usually well tolerated alternative to combination therapy. However, close monitoring of the patient's response is essential. Early empirical antifungal therapy also remains one of the prerequisites for a successful outcome in the management of neutropenic fever. Safer and more effective antifungal agents are urgently needed. In the future haematopoietic growth factors and other new techniques, such as peripheral blood progenitor cell transplantations, are likely to play a role in the early prophylaxis and management of severe neutropenic infective episodes. Future anti-infective strategies in the neutropenic host may not only lie with antibiotics, but also encompass successful modulation of host defences.

Anti-Bacterial Agents↗

Life span is prolonged in food-restricted autoimmune-prone (NZB x NZW)F(1) mice fed a diet enriched with (n-3) fatty acids.

Moderate food and/or energy (calorie) restriction delays age-related immune dysfunction and prolongs life span in multiple animal models. The amount and type of dietary fatty acids can also profoundly affect life span. Marine-derived fish oils contain (n-3) fatty acids, which have potent anti-inflammatory properties. We therefore examined the influence of food restriction (40% overall reduction in intake of all dietary components) combined with substitution of fish oil for corn oil in a factorial design. Autoimmune-prone (NZB x NZW)F(1) (B/W) mice, which develop fatal autoimmune renal disease, were used. The food-restricted/fish oil diet maximally extended median life span to 645 d (vs. 494 d for the food-restricted corn oil diet). Similarly, fish oil prolonged life span in the ad libitum-fed mice to 345 d (vs. 242 for the ad libitum/corn oil diet). Increased life span was partially associated with decreased body weight, blunting renal proinflammatory cytokine (interferon-gamma, interleukins-10 and -12 and tumor necrosis factor-alpha) levels and lower nuclear factor-kappaB (NF-kappaB). Reductions in NF-kappaB were preceded by enhanced superoxide dismutase, catalase and glutathione peroxidase activities. These findings demonstrate the profound additive effects of food restriction and (n-3) fatty acids in prolonging life span in B/W mice. These observations may have additional implications in the management of obesity, diabetes, cancer and/or the aging process.

Analysis of Variance↗

The clinical consequences of secondary hyperparathyroidism: focus on clinical outcomes.

Secondary hyperparathyroidism (SHPT) is a common occurrence in patients with chronic renal failure and is characterized by excessive serum parathyroid hormone (PTH) levels, parathyroid hyperplasia and imbalances in calcium and phosphorus metabolism. PTH acts as a uraemic toxin and it may be responsible for the following long-term consequences: renal osteodystrophy; non-skeletal abnormalities, including severe vascular and heart valve calcification; alterations in cardiovascular structure and function; immune dysfunction; and renal anaemia. The risk of developing SHPT is not the same for all uraemic patients. Black patients appear to have a higher risk of developing SHPT than Caucasian patients, and patients with diabetes have a lower risk than non-diabetic patients. Current treatments include dietary phosphate restriction, oral phosphate binders, vitamin D and its analogues, and, in severe cases, parathyroidectomy. These treatments do not provide optimal treatment for many patients, and compounds that directly inhibit PTH secretion may prove a major step forward in the treatment of SHPT.

Animals↗

Risk factors for non-Hodgkin's lymphomas in acquired immunodeficiency syndrome (AIDS)

The possibility that an agent in addition to the human immunodeficiency virus (HIV) may contribute to the etiology of non-Hodgkin's lymphoma in persons with acquired immunodeficiency syndrome (AIDS) was studied using participants from the Multicenter AIDS Cohort Study (MACS) of homosexual and bisexual men enrolled in 1984-1985 and also in 1987-1991. A nested case-control analysis was conducted. The primary source of information on potential exposures and characteristics of the participants was the baseline study entry interview that was conducted prior to the development of AIDS. A total of 84 cases of non-Hodgkin's lymphoma were identified and compared with 527 participants who developed AIDS but had no evidence of cancer. The groups were similar for most sociodemographic characteristics as well as sexual activity and past history of antecedent illnesses. Although the non-Hodgkin's lymphoma cases reported less frequent use of recreational drugs and cigarettes compared with other persons with AIDS, these differences were not significant. Non-Hodgkin's lymphoma cases reported more frequent intake of aspirin during the week before the interview. However, there were no differences between the comparison groups for long-term aspirin intake or intake of other analgesics. The absence of any specific and strong association between non-Hodgkin's lymphoma and the various behavior-related activities and exposures considered in this analysis suggests that these factors are not related to a second agent in the etiology of HIV-induced non-Hodgkin's lymphoma. The possibility that a very common agent in this study population or that differences in the nature of the immune dysfunction resulting from HIV infection could act as a cofactor for HIV-induced non-Hodgkin's lymphoma cannot be excluded.

Adult↗

Prognostic factors for all-cause mortality among hemophiliacs infected with human immunodeficiency virus.

To identify the prognostic significance of hemophilia- and virus-related factors, the authors undertook a survival analysis among 644 human immunodeficiency virus (HIV)-infected subjects enrolled in the Multicenter Hemophilia Cohort Study between 1985 and 1993. Acquired immunodeficiency syndrome (AIDS) was the leading cause of death, followed by hemorrhage and hepatic disease. Adverse prognostic factors included older age and CD4-positive lymphocyte values below 14 percent either at entry (age-adjusted mortality rate ratio (RR) = 6.4, 95% confidence interval (CI) 3.4-12.1) or after entry (time-dependent RR = 4.2, 95% CI 2.6-6.7); indeterminate antibody responses to hepatitis C virus (RR = 3.0, 95% CI 1.8-5.0); and inhibitory antibodies to factor VIII concentrates (RR = 1.8, 95% CI 1.1-3.1). Indeterminate hepatitis C virus status was associated with mortality from hepatic disease but not with AIDS mortality. Factors that were not prognostic included duration of HIV infection, hepatitis B virus infection, and other hemophilia variables. These findings suggest that fatal liver disease among coinfected subjects with an indeterminate hepatitis C virus status is probably related to an insufficient humoral response secondary to HIV immune dysfunction and that the risk of death among HIV-infected subjects is best evaluated with age and duration of low CD4 percentage.

Acquired Immunodeficiency Syndrome↗

Immunoglobulin responses to experimental silicosis.

Silicosis is a crippling fibrotic lung disease induced by inhalation of crystalline silica. One feature of silicosis is systemic and pulmonary immune dysfunction characterized in part by elevations in serum and bronchoalveolar lavage (BAL) immunoglobulins. A major specific aim of the current report was to demonstrate that an experimental model of silicosis previously well characterized for the development of pulmonary inflammation and fibrosis would also exhibit increased levels of serum and BAL IgG and IgM similar to those of human silicosis. We also sought to document the anatomic compartments responsible for these immunoglobulin responses. To address these specific aims, we compared levels of IgG and IgM in serum and BAL from rats with experimental silicosis induced by inhalation of silica with levels of these immunoglobulins in titanium dioxide (TiO(2))- and sham (air)-exposed controls. The ability of mononuclear cell populations from lung, lung-associated lymph node, and spleen to produce IgG and IgM ex vivo were also compared. We found that experimental silicosis was associated with elevated IgG and IgM levels in blood and BAL relative to the control groups. Our findings also suggested that draining lung-associated lymph nodes (LALN) were the most important sites for increased IgG and IgM production in experimental silicosis, with lungs contributing to a lesser degree. Increased production in the LALN appeared related to marked expansion in total numbers, but not relative proportion, of B lymphocytes.

Administration, Inhalation↗

In vivo manipulation of endogenous metallothionein with a monoclonal antibody enhances a T-dependent humoral immune response.

Metallothionein (MT) is a small stress response protein that can be induced by exposure to heavy metal cations, oxidative stressors, and acute phase cytokines that mediate inflammation. In previous experiments, we have shown that exogenous MT can affect cell proliferation, macrophage and cytotoxic T lymphocyte function, and humoral immunity to T-dependent antigens. In the studies described here, we have explored the effect of a monoclonal anti-MT antibody (clone UC1MT) on the role that endogenous MT plays in the humoral immune response. In vivo injection of UC1MT significantly increased the humoral response to simultaneous challenge with ovalbumin (OVA). In contrast, mice immunized with OVA in the presence of an isotype-matched antibody control (MOPC 21) showed no change in the anti-OVA humoral response. The predominant anti-OVA response that was enhanced by UC1MT treatment was the IgG(1) response; the IgG(2a) anti-OVA response was not altered by UC1MT treatment. UC1MT treatment increased the numbers of IgG anti-OVA secreting cells as measured by ELISPOT assay, suggesting that blocking the effects of MT synthesized during the immune response augments the differentiation of antigen-specific plasma cells. The percentages of T and B cells in the spleens of animals from each treatment group were not significantly different, suggesting that this regimen of UC1MT treatment does not significantly affect hematopoiesis, but rather alters antigen-induced differentiation of lymphocytes. These observations are compatible with previous results from our laboratory that suggest that endogenous MT synthesized during the normal immune response or as a consequence of toxicant exposure suppresses in vivo immune function. In light of the fact that significant amounts of MT can be synthesized during toxicant exposure, manipulation of MT levels with an anti-MT antibody may ultimately represent an important therapeutic approach to the treatment of immune dysfunctions that result from toxicant exposure.

Animals↗

Calcium-mediated activation of c-Jun NH2-terminal kinase (JNK) and apoptosis in response to cadmium in murine macrophages.

Cadmium is a well-known carcinogenic and immunotoxic metal commonly found in cigarette smoke and industrial effluent. An altered intracellular calcium ([Ca(2+)](i)) level has been implicated in the pathophysiology of immune dysfunction. The present study was designed to determine the possible involvement of calcium (Ca(2+)) and mitogen-activated protein kinases (MAPKs) signaling pathways on cadmium-induced cell death in J774A.1 murine macrophage cells. Cadmium caused a low-amplitude [Ca(2+)](i) elevation at 20 microM and rapid and high-amplitude [Ca(2+)](i) elevation at 500 microM. Exposure to cadmium dose-dependently induced phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and deactivated p38 MAPK. Use of the selective JNK inhibitor SP600125 suggested that activation of JNK is pro-apoptotic and pro-necrotic. Buffering of the calcium response with 1,2-bis-(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxy-methyl) ester (BAPTA-AM) and ethylene glycol-bis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) completely blocked cadmium-induced apoptotic response. The pretreatment of cells with BAPTA-AM and EGTA suppressed the cadmium-induced cell injury, including growth arrest, mitochondrial activity impairment, and necrosis, and it also recovered the cadmium-altered JNK and p38 MAPK activity. Chelating [Ca(2+)](i) also reversed cadmium-induced hydrogen peroxide generation, suggesting that production of reactive oxygen species (ROS) is related to [Ca(2+)](i). The present study showed that cadmium induces a [Ca(2+)](i)-ROS-JNK-caspase-3 signaling pathway leading to apoptosis. Furthermore, cadmium-induced [Ca(2+)](i) regulates phosphorylation/dephosphorylation of JNK and p38, and it modulates signal transduction pathways to proliferation, mitochondrial activity, and necrosis.

Animals↗

Pure red cell aplasia and the syndrome of multiple endocrine gland insufficiency.

A 26-year-old female with the syndrome of multiple endocrine gland insufficiency developed pure red cell aplasia. A clinical remission of the pure red cell aplasia was induced with prednisone and cyclophosphamide therapy. The occurrence of these two disorders in a single patient allows speculation on a possible defect in immune surveillance leading to multisystemic immune dysfunction in this patient.

Adolescent↗

Increased synthesis and production of prostaglandin E2 by monocytes from drug addicts with AIDS.

We analysed the production of prostaglandin E2 (PGE2) by monocytes in 11 drug addicts with AIDS and opportunistic infections and in 13 controls. In three patients and six controls we isolated the PGE2 fraction from culture supernatants of purified monocytes (greater than 95%) incubated in medium containing (3H) arachidonic acid, using silicic acid columns. In two of three patients PGE2-fraction values (21.9 and 21.6 pmol/g protein) were significantly higher than controls (10 +/- 4). In eight AIDS patients and seven controls, PGE2 levels were determined by high-performance liquid chromatography and radioimmunoassay (HPLC and RIA). In three out of eight patients PGE2 levels were markedly higher (736, 419 and 208 pg/ml) than the mean + 2 s.d. values from controls (73 +/- 51). We tested the effect of PGE2 on the production of interleukin-2 by normal phytohemagglutinin-stimulated peripheral blood lymphocytes (PBL). There was a significant suppression of interleukin-2 production by PGE2 released from AIDS monocytes. PGE2 may be one of the factors involved in the severe immune dysfunction associated with AIDS.

Acquired Immunodeficiency Syndrome↗

Sequential autonomic function tests in HIV infection.

Cardiovascular autonomic function tests were carried out on 22 men at varying stages of HIV infection. Thirteen were asymptomatic, seven had persistent generalized lymphadenopathy, and two had Kaposi's sarcoma. Pupil cycle times were also measured. Except for one subject with definite autonomic abnormalities, all the rest had almost normal test results. There were no correlations between individual tests of immune function and the autonomic test results. The tests were repeated 9-18 months later in 12 men, four of whom were taking zidovudine at that time. Although there was evidence of progression of HIV-associated immune dysfunction, there was no significant deterioration in autonomic function. In the single patient with abnormal autonomic function, these changes appeared to reverse on treatment with zidovudine.

Adult↗

Immunological and virological markers in individuals progressing from seroconversion to AIDS.

Six men were selected from a large cohort of homosexual men participating in a study on HIV infection that was followed from seroconversion to AIDS. The patients were studied retrospectively for immunological functions of T cells, T-cell subset distribution and biological phenotype of HIV. A severe decrease in anti-CD3 monoclonal antibody (MAb)-induced T-cell proliferation at seroconversion was observed in two out of six men. After this acute phase, CD4+ T-cell numbers were in the normal range in the early asymptomatic period; the proliferative response was subnormal, whereas the capacity to generate cytotoxic T cells (CTL) was normal. From seroconversion on, CD4+CD29+ memory T-cell numbers were decreased to approximately 50% of normal values, which may contribute to loss of T-cell reactivity. In the asymptomatic phase only slow-replicating non-syncytium-inducing HIV variants were observed. The T-cell proliferative response further declined with the depletion of naive CD4+ CD45RA+ T cells and CD4+ T-cell numbers started to decline. This second decrease in T-cell function coincided with the emergence of more rapidly replicating, often (four out of six) syncytium-inducing variants. At diagnosis of AIDS, T-cell proliferation and CD4+ T-cell numbers were extremely low in five out of six patients and CTL function had declined in three out of five individuals tested. Circulating CD8+ cells had gradually shifted to an immature CD38+CD28- phenotype. Our findings support the theory that HIV-induced immune dysfunction allows for the emergence of virulent HIV variants associated with CD4+ cell loss and disease.

Acquired Immunodeficiency Syndrome↗

Diagnostic value for culture of cerebrospinal fluid from HIV-1-infected individuals for opportunistic viruses: a prospective study.

OBJECTIVE: To investigate the diagnostic value of cerebrospinal fluid (CSF) culture for opportunistic viruses from HIV-1-infected individuals. METHODS: A 4-year prospective study was conducted using a participant population consisting of 186 HIV-1-infected individuals without neurologic disease, 73 HIV-1-infected individuals with encephalopathy, myelopathy, and/or peripheral neuropathy, and 10 controls. CSF samples recovered at 1-year intervals were subjected to virus culture using technique commonly used in the clinical laboratory setting. RESULTS: CSF samples obtained from only 15 of the 269 (5.6%) participants yielded an opportunistic virus upon culture. Cytomegalovirus, herpes simplex virus types 1 and 2, adenovirus, and presumptive enteroviruses were identified. No consistent correlation was observed between the detection of an opportunistic virus within a CSF sample and the presence or future development of neurologic disease. However, a significant correlation was observed between culture of virus from CSF and the future development of abnormal CD4+ (chi 2, P = 0.0286) and CD8+ (chi 2, P = 0.0018) lymphocyte counts in HIV-1-infected participants without neurologic disease. CONCLUSION: These results show that culture of CSF to screen for opportunistic viruses is neither diagnostic nor predictive of neurologic disease in HIV-1-infected individuals. Nevertheless, the presence of virus within CSF may be an indicator of HIV-1-mediated immune dysfunction and a predictor for future development of abnormal CD4+ and/or CD8+ lymphocyte counts.

AIDS-Related Opportunistic Infections↗

Live attenuated, nef-deleted SIV is pathogenic in most adult macaques after prolonged observation.

OBJECTIVE: A live attenuated SIV vaccine strain, termed SIVmac239Delta3 and containing large deletions in, and the negative regulatory element, was previously shown to cause AIDS mostly in monkeys vaccinated as infants. In the present study, we demonstrate that SIVmac239Delta3 is pathogenic in most vaccinated adult monkeys, given enough time. METHODS: Eleven rhesus macaques vaccinated as adults with SIVmac239Delta3 were followed for extended periods (up to 6.8 years). RESULTS: We found signs of immune dysregulation in all 11 adult vaccinees. All animals developed persistently inverted CD4 : CD8 T-cell ratios, seven (64%) had persistent recurrent viremia, and six (55%) had decreased CD4 T-cell counts (< 500 x 10 cells/l). Further signs included low CD4CD29 lymphocyte subsets, loss of anti-Gag antibodies, anemia, thrombocytopenia, wasting, and opportunistic infections. Two adult vaccinees (18%) subsequently developed AIDS. Development of chronic, recurrent viremia with plasma viral RNA loads > or = 10 copies/ml and cytoviremia was a poor prognostic sign. CONCLUSION: Our data demonstrate that with time, a live attenuated, multiply deleted SIV vaccine can cause immune dysregulation in most vaccine recipients, even in initially immune competent, healthy adults. Immune dysfunction can progress to full AIDS. However, pathogenic effects became evident only several years after vaccination. Thus, mass vaccination of humans with similarly constructed live attenuated HIV vaccines, recently suggested for countries with high HIV-1 transmission rates, seems contraindicated.

Animals↗

Cytokine networks are pre-activated in T cells from HIV-infected patients on HAART and are under the control of cAMP.

OBJECTIVE: Cytokines seem to play a critical role in HIV infection. The cAMP/protein kinase A (PKA) type I pathway is shown to be hyper-activated and contributes to T-cell immune dysfunction in HIV infection. Here, we analysed firstly the levels of cytokine gene expression in unstimulated CD3+T cells from HIV-infected patients on HAART, and secondly the regulation of cytokine and cytokine-related genes by cAMP agonist and antagonist in anti-CD3 activated T cells in order to understand their effects on cytokine networks. METHODS: Cytokine Macro Array and real-time RT-PCR techniques were used to study cytokine gene expression in T cells of HIV-positive patients. RESULTS: Of the cytokine-related genes analysed 45% were expressed at twofold or higher levels in unstimulated T cells from HIV-infected patients as compared with healthy controls, and one-third of these genes were hypo-responsive upon activation as compared with controls. Furthermore, cAMP modulated levels of expression of a number of cytokine-related genes differently in patient and control T cells. CXCR4, CCR5 and amphiregulin were up-regulated by cAMP agonist, whereas other cytokine-related genes including macrophage inflammatory protein 1 beta, tumour necrosis factor-alpha and lymphotoxin-beta were markedly down-regulated by cAMP agonist in T cells from both HIV-infected patients and controls. Moreover, members of the chemokine/chemokine receptor family were over-represented among genes regulated by cAMP agonist/antagonist in patient T cells. CONCLUSIONS: Our data indicate that T cells from HIV-infected patients are in a pre-activated state and that a set of cytokine genes is hypo-responsive to activation and under tonic regulation by cAMP in these T cells.

Adult↗

Reactive arthropathy and autoimmunity in non-HIV-associated immunodeficiency.

The spectrum of arthropathy in non-HIV immune deficiency states includes arthritis due to prevalent infectious pathogens and autoimmunity that may in some instances be triggered by microorganisms. Joint symptoms may be clinical manifestations of disease, or they may develop later during therapy for immunodeficiency. Pathogenesis can be related to occult infection, loss of mucosal barrier function, defective clearance of immune complexes, or aberrant immune responses. Proper treatment includes an appreciation of likely pathogens, an understanding of the nature of immunologic deficits, and rigorous exclusion of immune dysfunction that may be secondary to treatment.

Animals↗

Topical interferon alpha-2a treatment of herpes simplex keratitis resistant to multiple antiviral medications in an immunosuppressed patient.

The treatment of herpes simplex keratitis has ranged from simple debridement to the use of prototypic antiviral agents specific to the herpes family, such as acyclovir. The various treatment modalities for dendritic keratitis, for the most part, have been effective. However, in recent years numerous reports of antiviral-resistant strains of herpes simplex have appeared, particularly in immunocompromised patients receiving chronic acyclovir. Interferon has been proposed as a possible treatment adjunct in these cases. We report the case of a 46-year-old man on chronic immunosuppressive and acyclovir therapy after a renal transplant who developed ulcerative keratitis due to a strain of herpes simplex virus that was resistant to multiple antiviral agents both in vivo and in vitro. After 7 weeks without improvement on multiple treatment regimens, including trifluridine, vidarabine, debridement, and topical and systemic acyclovir, interferon alpha-2a was added to topical acyclovir therapy, and the keratitis quickly resolved. Topical interferon alpha-2a appears to be an effective treatment adjunct for refractory herpes simplex keratitis in patients with cell-mediated immune dysfunction and subsequent lack of endogenous interferon. Its value in nonimmunocompromised patients remains to be determined.

Acyclovir↗

Thyrotropin-releasing hormone in critical illness: from a dopamine-dependent test to a strategy for increasing low serum triiodothyronine, prolactin, and growth hormone concentrations.

OBJECTIVE: The aim of this study was to examine the effect of dopamine infusion on the thyrotropin (TSH), thyroid hormone, prolactin, and growth hormone responses to thyrotropin-releasing hormone (TRH) in critically ill patients. DESIGN: Prospective, randomized, controlled, open-labeled clinical study. SETTING: The intensive care unit, University Hospital Gasthuisberg, Leuven, over a 1-month period. PATIENTS AND INTERVENTIONS: In 15 critically ill patients receiving dopamine treatment (5 micrograms/kg/min) for a mean of 43.3 +/- 1.2 (SEM) hrs after trauma or cardiac surgery, we studied the TSH, thyroid hormone, prolactin, and growth hormone responses to the administration of two consecutive intravenous TRH boluses of 200 micrograms, with a 6-hr interval. The dopamine infusion was continued in the control group and discontinued in the study group. Serum concentrations of TSH, prolactin, and growth hormone were measured before and 20, 40, 60, and 120 mins after TRH administration. Serum concentrations of thyroxine (T4), triiodothyronine (T3), reverse T3, and thyroid hormone binding globulin were determined before and 120 mins after each TRH injection. MEASUREMENTS AND MAIN RESULTS: There was a > 100-fold interindividual variation in the baseline TSH concentration and in the TSH peak value after TRH administration. Two consecutive doses of TRH evoked a mean 16% increase in serum T4 concentration (p = .003) and a mean 47% increase in T3 (p = .001), whereas serum reverse T3 and thyroid hormone binding globulin values remain unaltered. Each of the TRH boluses increased serum growth hormone concentrations in the continued dopamine and discontinued dopamine groups, by a median of 60% (p = .001) and 68% (p = .001), respectively. Three hours after dopamine withdrawal, there was a three-fold increase of the peak TSH response (p = .001), a higher T3 response (p = .01), and a ten-fold increase of the peak prolactin value (p = .001) in response to TRH administration. CONCLUSIONS: The TSH response to TRH administration in critical illness presents a striking interindividual variation and dopamine dependent. Repeated TRH administration results in a repetitive increase of TSH, prolactin, growth hormone, T4, and T3, without increasing reverse T3. These observations point toward a potential for TRH as a strategy for reversing the euthyroid sick syndrome, growth hormone deficiency, and immune dysfunction associated with critical illness.

Adolescent↗