Inhaled CS in acute asthma

Genomic Effects of CS

The mechanisms of action of CS on the inflammatory process are complex. The classic antiinflamma-tory effects implicate the activation or repression of multiple genes involved in the inflammatory process. Thus, CS produce their effects on cells by activating glucocorticoid receptors that alter transcription through direct DNA binding or transcription factor inactivation. As a consequence, CS increase the synthesis of antiinflammatory proteins, or inhibit the synthesis of many inflammatory proteins through suppression of the genes that encode them. This

effect is also denominated genomic because it implies the participation of cellular genome. The length of time between CS entry into the cell and the production of new proteins is in order of hours or still days.

This fact is in concordance with clinical evidence that shows a 4 to 12 h delay to be able to detect beneficial 

effects of SCS.

Rapid Nongenomic Effects of CS

Although the major part of the investigation has been performed in the last decade, already in 1942 Hans Selye13 observed that some CS-induced effects (anesthesia) only minutes after their application, constituting the first notification of a nongenomic effect of CS. Two decades later, acute cardiovascular effects of aldosterone (after 5 min of its administration) were reported in humans.

 Lately, CS have also been shown to acutely decrease nasal itching in allergic rhinitis patients.15 These rapid effects are initiated by specific interactions with membrane-bound or cytoplasmic CS receptors, or nonspecific interactions with the cell membrane, and the responses are much more rapid (seconds or minutes). 

Membrane receptor inactivation has been shown to induce rapid effects on a variety of second messenger systems.

 In addition, CS could bind other receptors, ion channels, enzymes, or transporters.

More recently, research has been focused in the nongenomic effects of ICS on airway smooth-muscle tone, and particularly in the study of the mucosal blood flow of asthmatic and healthy people. Thus, membrane binding sites for CS have been demonstrated in smooth-muscle cells isolated from human airway blood vessels. Studies also show that asthmatics present a significant increase in airway mucosal blood flow in comparison with healthy subjects (24 to 77% higher in asthmatics), and that inhalation of fluticasone (880 g) or budes-onide (400 g) decreases blood flow in both groups. This effect is transient, reaching a maximum approximately 30 min after inhalation, and returning to basal values at 60 to 90 min. 

This blood flow decrease is dose dependent, with a greater effect in asthmatics than in healthy subjects. Finally, it was not specific for fluticasone or budesonide, and also it was demonstrated for beclomethasone. However, fluticasone and budesonide cause greater effect than beclomethasone.18 Evidence suggests that CS decrease airway blood flow by modulating sympathetic control of vascular tone, potentiating noradrenergic neurotransmission in the airway vasculature.

 After release from sympathetic terminals, norepineph-rine must be taken up by postsynaptic cells from CS-induced vasoconstriction. Furthermore, this decrease of airway blood flow is likely to enhance the action of inhaled bronchodilators by diminishing their clearance from the airway  Thus, simultaneous administration of ICS and bronchodilators could be of clinical significance.

In summary, CS can show two different effects on acute asthma patients :

(1) the classic antiinflammatory or genomic action, involving the modification of gene expression, that occurs with a time lag of hours or days; and (2) the nongenomic action, with has a rapid onset (minutes), is reversible (short duration), and is dose dependent. 

Finally, a direct relationship was observed between the ICS-induced airway blood flow decrease and predrug airway blood flow.

 These vascular effects of ICS on airway blood can be expected to have therapeutic implications in the management of acute asthma, and its characteristics are fundamental to establish the optimum dose and timing of administration in the emergency department (ED) setting. 

Accordingly, ICS would have to be administered simultaneously with bronchodilators in high and repeated or sequential doses as a way to obtain and maintain the effect throughout the time. Since ICS induce vaso-constriction peaks between 30 and 60 min after drug administration, their use in intervals not 30 min seems adequate. The objective of this review was the analysis of the best evidence available on the early clinical impact of ICS for acute asthma patients.

Stages of iron deficiency anemia

Clearly, as iron deficiency develops, it will go through various stages, each with its own pattern.

1. IN THE EARLIEST STAGE, iron is gradually being lost from the stores. The serum iron studies are still normal, the FBC appearance is normal. This is called LATENT IRON DEFICIENCY, and there is no specific clinical or laboratory feature to suspect it. It is only if a bone marrow aspirate were done – and clearly there would not normally be any indication for doing it – that one would see that stainable iron and sideroblasts are reduced, and ultimately absent. If one were really suspicious about the possibility of latent iron deficiency, one would still need considerable justification for submitting a patient to aspiration. However, red cell protoporphyrin levels (increased) are an acceptable substitute. Transferrin receptor levels are raised, and the RDW at this stage is still normal. As indicated above, this stage can last for a very variable time, depending on the balance between

a) The rate of blood loss and 

b) The amount of dietary iron (and in what form), the efficacy of absorption, and the quality of the bone marrow

2. Once IRON STORES ARE DEPLETED, the following changes are seen:

a) Serum iron decreases steadily.  

b) Transferrin increases steadily. 

c) % Saturation falls steadily. 

d) Stainable iron and sideroblasts are absent from the marrow. 

e) The RDW rises. 

f) A right shift of the neutrophils gradually develops.

3. It is only now that IRON DEFICIENCY AS SUCH is established:

a) The % saturation is well below 15.

 b) The red cells become microcytic. 

c) The red cells start off by showing anisochromia then full-fledged hypochromia. 

d) The RDW tends to diminish. 

e) Plus the other changes as mentioned before.

Clinical case 1

An 8-month-old boy presents to the emergency department with a rightsided facial droop for 1 day and blackish bruising around both his eyes resembling raccoon eyes for a week. His mother reports that the childhadfallenfromacouch2weeks earlier. The child has also been fussy, withdecreasedfeedingfor3days.He has no history of fever, and findings from a review of his systems are otherwise unremarkable. Medicalhistory, family history, and social history are also unremarkable. On examination, the child is fussy but alert. Vital signs are normal: temperature, 98.7°F (37.0°C); heart rate, 108beatsperminute;respiratoryrate, 32 breaths per minute; and blood pressure, 98/60 mmHg. Anterior fontanelle is soft and flat. There is right-sided ptosis and drooping of the right side of the mouth, especially apparent when the child cries. There arenootherfocaldeficits,andtherest of the neurologic examination findings are normal. Ecchymoses are seen extending, approximately a centimeter, circumferentially around both eyes. The liver is firm and palpable 3 cm below the right costal margin. The rest of the physical examination findings are normal. Initiallaboratoryevaluationreveals the following: hemoglobin, 7.7 g/dL (77 g/L); mean corpuscular volume, 80.7 fL; white blood cell count, 12,390/mL (12.39 109/L); and platelet count, 298 103/mL (298 109/L). Computed tomography (CT) of the head without contrast revealsnoevidenceofintracranialbleeding. Further investigations reveal an

explanation for the child’s constellation of symptoms and anemia.

   What do you think these investigations which have been requested?

What is your diagnosis?


ANSWER



The findings of raccoon eyes, normocytic anemia, and hepatomegaly prompted abdominal ultrasonography, followed by CT of the abdomen and pelvis with contrast, which revealed a left suprarenal mass and masses in the liver suggestive of metastasis. 

Excisional biopsy of the mass confirmed the diagnosis of neuroblastoma with favorable histologic features, and there was no amplification of the N-myc gene. 

Urine catecholamine studies revealed elevation of the vanillylmandelic acid to creatinine ratio, homovanillic acid to creatinine ratio, and dopamine to creatinine ratio.

Bilateral bone marrow biopsies revealed metastatic neuroblastoma.

 A meta-iodobenzylguanidine scan revealed marked uptake in the temporal bones bilaterally, which explained the right facial nerve paralysis. The scan also showed increased uptake in the liver, left suprarenal mass, skull base, ribs, vertebral column, and the long bonesoftheupperandlowerextremities. These findings confirmed the diagnosis of a stage IV neuroblastoma.

 Facial nerve paralysis is most commonly idiopathic, in which case it is called Bell palsy. 

Known causes of nerve VII paralysis include the following:

 (1) infections such as herpes zoster reactivation, herpes simplex virus, Lyme disease, and human immunodeficiency virus


 (2) central nervous system disorders such as stroke and Guillain-Barre syndrome

(3)conditions such as mastoiditis and cholesteatoma
 (4) neoplasms such as parotid gland tumors,centralnervoussystemleukemia, and tumors with central nervous metastasis

(5)sarcoidosis(Heerfordtsyndrome)
(6) head injury. 

Raccoon eyes or bilateral ecchymoses are a classic presentation of neuroblastoma, seen because of periorbital hemorrhage caused by orbital metastasis. However, raccoon eyes are most commonly caused by basal skull fractures or basilar head bleeds and should raise a red flag for child abuse.

 Normocytic anemia in infancy can be due to transient erythroblastopenia of infancy, bacterial or viral infections, hemorrhage, red blood cell membrane or enzymatic defects, bone marrow disorders, and hemolysis due to hemoglobinopathies. Isolated normocytic anemia should also raise suspicion for a malignant tumor as in our patient, who likely had hemorrhage in his tumor.

Pediatric clinical cases

A 3-year-old girl presented to A
þ E with a 1 week history of general flu-like illness and a 1 day history of painful erythematous nodules on her shins. She had no significant past medical history. Her grandfather had previously had HSP but there was no other family history. There was no history of foreign travel and she was not in regular contact with animals. On examination she was miserable and pale but well-nourished and refusing to weight-bear. She screamed if anyone went near her legs. The rest of the examination was normal.
Blood tests showed raised inflammatory markers: CRP 107, WCC 21, Neutrophils 15.5. CXR was unremarkable.
Q1. What is this rash?
a) HenocheSchonlein purpura
b) Chicken Pox
c) Discoid eczema
d) Erythema nodosum
e) Erythema multiforme
Q2. What are the causes of this rash?
a) Inflammatory Bowel Disease
b) Streptococcal infection
c) Sarcoidosis
d) Campylobacter
e) Salmonella
Q3. Choose True or False for the following statements:
a) These lesions leave scars
b) They may continue to erupt for 10 days
c) The lesions usually resolve within a week
d) The lesions are prone to ulceration

e) It is a disorder of the subcutaneous fat


answer


A1 d) This rash is Erythema nodosum. It is a type of pan-niculitis. There is often no obvious cause. The most common cause in children is a streptococcal infection, specifically group A streptococcus secondary to tonsillitis. The nodules can appear 2e3 weeks after a streptococcal throat infection.
This child was treated with IV Augmentin and within 2 days the rash started to fade and the pain eased. A throat swab grew Group A Streptococcus.

A2 a,b,c,d,e) Causes: Streptococcal infection Sarcoidosis
Inflammatory Bowel Disease Pregnancy Tuberculosis Chlamydia

Mycoplasma pneumoniae Yersinia enterocolitica Salmonella Campylobacter
Drug reaction: antibiotics or the combined oral contraceptive pill
Lymphoma and leukaemia
Erythema nodosum is rare. It affects between two and three people in every 10,000 people per year in the UK. It is most common between the ages of 20 and 35 but it can occur at any age.
Usually the first sign of erythema nodosum is flu-like symptoms. 

This happens before the nodules appear and may make a child feel generally unwell for a few weeks. Possible symptoms include a fever, a cough and even weight loss. They may also have aching joints, stiffness and general aches and pains. Their joints may become swollen. Ankle, knee and wrist joints are most commonly affected but any joint can be painful. Aching legs and joints can last for a number of weeks, or even months, after the nodules have appeared.
The nodules (rounded lumps) that occur in erythema nodosum can measure between two to six centimetres across. The shins are the most common site. Other common sites are on the arms, thighs and trunk but nodules can occur anywhere on the body.

Each nodule tends to last for about 2 weeks but new nodules can continue to appear for up to 6 weeks. When the nodule first appears it is usually red, hot and firm to the touch. As the nodule begins to fade, it looks more like a bruise, turning blue and then yellowish. It usually takes some weeks for the nodules to heal completely. They do not leave any scarring