Thalamus and Outline of Sensory System.

                                      Thalamus and Outline of the Sensory System

                                                PKGhatak, MD

Thalamus:

The thalamus is a collection of neurons in the midbrain; in fact, there are two in number, the thalami. Thalami are placed close together in the middle of the midbrain, separated by the Third Ventricle containing CSF (cerebrospinal fluid). They are the mirror image of each other. The thalamus is the initial sensory receiving center of all the incoming information from the body, namely 1. the somatic sensation from the skin - touch, pain, cold and hot sensations. 2. Proprioceptor sensation of the body - positions of limbs, head in relation with each other. 3. visceral sensation from chest, abdomen and pelvis - the sense of bloating, cramps, pain and discomfort. 4. special senses from eyes, ears, tongue - visual, auditory, taste but not the smell sensation.

Thalamus relays the sensory input received from different parts of the body to specialized areas of the cerebral cortex for detailed analysis, at the same time receives communications from the cerebral cortex. The interplay of this back and forth information between the thalamus and cerebral cortex determines the final sensory appreciation, the body's response to sensory information, memory formation and association. Thalamus also generates local sleep patterns - namely sleep and wake rhythm during the non-rapid eye movement sleep.

To achieve these functions, the thalamus is extensively connected with all major nuclei of the midbrain - hypothalamus, amygdala, hippocampus, etc., and the cerebellum, medulla oblongata and cerebral cortex.

There are 6 functional groups of thalamic nuclei. These are 1. Anterior thalamic nuclei- facing the forehead. 2. Lateral thalamic nuclei- facing towards the ear of the same side. 3. Medial nuclei - facing each other across the midline. 4. Paraventricular-located next to the 3^rd ventricle. 5. Interthalamic - making the connection between the two thalami. 6. Reticular a net-like nuclei is located at the bottom of the thalamus.

Anterior thalamic nuclei: Afferent fibers relay here from Limbic strictures and the medial mammary nucleus. Efferent fibers from the thalamus connect to the Cingulate gyrus, parahippocampal nuclei, the perforated substance and the limbic nuclei.

Function: Emotion, memory, alertness.

Lateral thalamic nuclei: Receives afferent fibers from Globus pallidus, substantial nigra. Efferent connection to the frontal lobe of the cerebral cortex, and the Interthalamic nuclei.

Function. Planning and initiating movement.

Ventral thalamic nuclei are the Ventrolateral and Ventromedial groups of nuclei.

Ventromedial: receives input from the contralateral cerebellum, the ipsilateral motor cortex.

Efferent output to the primary motor cortex and premotor cortex.

Function. Motor response and integration of sensory and motor functions.

Venteroposterior:

Afferent input from lateral spinothalamic and dorsal spinothalamic tracts. These are the main sensory receiving nuclei of the thalamus. Also, fibers from medial lemniscus and trigeminal thalamic sensory fibers end here.

Efferent output to the sensory parietal cortex, insular cortex.

Function. The initial sensation of pain, temperature, touch, discriminating touch, and conscious proprioception.

Other thalamic nuclei receive and communicate with various midbrain nuclei, different areas of the cerebral cortex and cerebellum.

Sensory system.

A general outline of the somatic sensory system consists of receptors, neurons, ascending tract in the spinal cord and hindbrain, and nerve centers.

 The Receptors are: -

Naked nerve ending. It is sensitive to pain stimuli. Ruffini endorgan records stretch sensation, deformities, warm temperature. The end bulb of Krouse detects cold, these are also present in the mucous membrane of the eyes, mouth and genitalia. Meissner's corpuscles are onion like layered receptors that receive slow vibration from the skin and bones and also touch sensation. Merkel discs receive light touch and two-point discriminating tactile sensations, sustained pressure and touch. Pacinian's corpuscles record deep pressures and fast vibrations. The hair follicle plexus is stimulated by the movement of hair. Muscle spindles record muscle contractions, cramps, and stretch sensation. Golgi tendon organ records the stretch produced in the tendons. Bulbous corpuscles are stimulated by the stretch of the capsule of joints.

A number of skin receptors are also present in joint capsules, tendons and bones.

Joint kinesthetic receptors. These are responsible for information generated from limbs and joints during movement.

Vestibular organs. Present in the middle ears, these receptors record position of the head on three dimensional axis.

 The Neurons: -

 The neuron with its long arm - afferent/axon, carries the impulse towards the central nerve center. The short arm of the neuron, called dendrons, makes a synaptic connection with the 2nd order neuron. The nerve bundles in the spinal cord take the impulses all the way up till they reach the medulla oblongata, then the fibers cross the midline to the contralateral thalamus. So, the thalamus of one side receives the sensory information from the opposite side of the body. The 3^rd order neuron of the thalamus carries the impulses to specific areas of the parietal sensory cortex of the brain located on the same side as the thalamus is located.

 The Pathways to the Thalamus:

The neurons for skin sensations are located in the dorsal root ganglion of the spinal nerves. The axons enter the spinal cord by the dorsal root. Thereafter the fibers make three ascending paths to the thalamus on the opposite side and end in the contralateral thalamus.

Pain, two-point discrimination touch, and vibratory sensation pathway.

Axion carrying the sensation turns upwards in the spinal cord along the posterior ascending column. Below the T6 level, ascending fibers are placed in the medial position, then fibers from each higher segment are placed lateral to the fibers already present – somatotopy organization. The fibers make synaptic connections with neurons called Nucleus Gracile located in the lower medulla. The second order neurons cross the midline - decussate in the medulla oblongata and ascend to the ventromedial nuclei of the contralateral Thalamus via the medial lemniscus.

The axon above the T6 level to C1 similarly ascends up the spinal cord lateral to the Ascending tract of Gracile. Similar somatotopy organization is present in this tract. At the lower medulla and fibers make synaptic connections with a collection of neurons called the Nucleus Cuneatus. Then follow the same path as the tract of Gracile. 

Cold/hot sensation and pain pathway:

1^st order neurons are the dorsal root ganglions. The axons enter the spinal cord via the posterior root and move up or down 1 or 2 segments, then make synapses with the second order neurons located in the posterior horn. The fibers cross the midline in front of the central spinal canal and then ascend upwards occupying a lateral position in the spinal cord known as the lateral spinothalamic tract. These fibers reach the ventromedial nuclei of the thalamus via the medial lemniscus and there they make synapses. The rest of the pathway is similar to tracts of Gracile and Cuneatus.

Crude touch and firm pressure pathway:

The layout is similar to the lateral spinothalamic tract except the 1^st order axons cross the midline immediately and synapse with the 2^nd order neurons. And that tract occupies a more anterior position in the spinal cord. The rest of the track follows the temperature path.

Proprioceptive sensory tract:

The 1^st order neurons are the dorsal root ganglions. The axons after entering the spinal cord take one of the three paths.

Those carrying proprioceptive destined to reach the conscious level follow the fibers of the somatic sensory fibers, traveling up along the tracts of the Gracile and Cuneatus. One big difference is that the proprioceptor fibers do not cross the midline and enter the ipsilateral cerebellum through the inferior cerebellar peduncle and make synaptic relay with the nuclei present in the vermis and para ventral nuclei of the cerebellum. The dendrons carry the information to the deep nuclei of the cerebellum, and the 3^rd order neurons carry the information to the thalamus and other midbrain nuclei.

Unconscious proprioceptor sensory information.

Below L2 Level.

Central axons of the 1^st order neurons end by making synapses with the posterior horn nuclei. The ascending fibers of the 2^nd order neurons immediately cross the midline in front of the spinal channel. Then ascend to the midbrain at the junction of the midbrain and medulla, then cross the midline again and enter the cerebellum through the superior cerebellar peduncle. The spinal cord location of these fibers is called the Anterior spinothalamic tract.

Above the L2 level and up to the T1 level.

The axons of the 1^st order neuron terminate in the Clarke nucleus of the posterior horn of the same side of the spinal cord. The ascending axons of Clarke nuclei remain on the same side of the spinal cord and travel up as the posterior spinocerebellar tract. Then, reaching the medulla enters the cerebellum through the inferior cerebellar peduncle.

Above T1 level.

The axons of 1st order neurons ascend with the Cuneatus tract and make synapses with accessory Cuneatus nuclei. The fibers enter the cerebellum through the inferior cerebellar peduncle.

 The Trigeminal nerve.

The skin of the forehead, face and lower jaw are innervated by the 5^th cranial nerve- The trigeminal nerve. The nucleus is known as the trigeminal ganglion located on the petrous process of the temporal bone. The second order neurons are located in a long structure extending from the upper cervical cord to the lower midbrain. The axons from these neurons cross the midline and join the medial lemniscus to the thalamus.

Visceral senses.

The general outlay of the sensory information reaching the brain is different. One reason is the viscera are not paired – one heart, one liver, one large gut and on the small intestine, etc. Only there are two lungs.

The second reason is that visceral sensations are carried both by the sympathetic and parasympathetic nervous systems. The parasympathetic system carries the general sensation and the sympathetic system carries general and also the pain sensation. There is no hard and fast distinction of senses into ipsilateral or contralateral representation in the thalamus or in the cerebral cortex. In most cases, the thalamus and the cerebral cortex area receive visceralsensory information from both sides of the body.

Parasympathetic visceral sensory system:

The receptors: The receptors are present in all the layers of the small and large intestines. Glands and solid organs likewise have several receptors.

The parasympathetic sensory outlay is a bit different from the general sensory system, again are of two groups - A. all viscera located in the thorax, abdomen including the medial 2/3^rd of the transverse colon, B. the lateral 1/3 of transverse colon, sigmoid colon, rectum, anal canal, urinary bladder, urethra and organ of sex.

A. Upper abdominal visceral path of parasympathetic:

The Vagus nerve.

Sensory information from the thoracic viscera, abdominal viscera, and the medial 2/3 rd. of the transverse colon is carried by the sensory division of the vagus nerve to the Nucleus Nodosa of the vagus situated in the medulla on the ipsilateral side.  The second order neuron of the vagus carries the sensation upward in Tactus Soliterious to both the Thalami. The 3^rd order neurons take that information to the sensory cerebral cortex.

B. Lower abdominal visceral parasympathetic:

 The Hypogastric nerve.

The afferent fibers of parasympathetic 1^st order neurons are located in the posterior horn of the T10 to S2 segments of the spinal cord. These fibers entering the spinal cord make synapse with the second order neuron of the parasympathetic system. They travel upwards to the medulla along with somatic sensory fibers in the Gracile tract and the end of the fiber in the sensory dorsal nucleus of the vagus.

  The Inferior hypogastric nerve.

The nucleus is located in the dorsal root ganglion of S2 to S4 segments. The axons travel along with the pelvic and pudendal nerves to innervate the remaining pelvic organs and sex organs. The upward journey starts with the fibers of the Gracile and ends in the sensory nuclei of the Vagus in the medulla.

Sympathetic sensory system.

Receptors. Similar to parasympathetic, sympathetic receptors are present from all layers of viscera and glands and in addition, unmedullated C-fibers carry pain sensation. The first-order neuron is located in the dorsal root ganglia of the entire spinal cord.

The pain of cutting, burning, crushing is not carried from the viscera but inflammation, necrosis, obstruction related pain is carried from the visceral wall by the undulated C-fibers of sympathetic nerves. On their onward journey to the spinal cord, the fibers accompany the sympathetic tract carrying efferent sympathetic stimuli.

 Sensation from eyes, lachrymal glands, nose, palate, and salivary glands.

 Sympathetic afferent fibers pass through the cervical sympathetic ganglia, then accompany the postganglionic sympathetic fibers. The fibers leave the sympathetic nerve and join the white rami to join the mixed spinal nerve and enter the spinal cord via the white rami by the dorsal root. It makes a synaptic connection with the thoracolumbar sympathetic neurons. The second order neurons carry the sensation along with the somatic senses of the thalamus.

 The sensory sympathetic innervation of the heart, the trachea, and the bronchi.

 The dorsal root ganglions of C4 to T5 segments carry sensory information and fibers pass through the celiac ganglion. Then the upward path is the same as above.

Innervation of the stomach, liver, bile duct, gall bladder, spleen, kidneys, pancreas and small intestine.

The T6 to T11 segments supply sensory fibers and the fibers pass through the superior mesenteric ganglion.

 The rest of the GI organs and pelvic organs send sympathetic sensory information.

 The sensory afferent fibers originate in T12 to L2 segments. The fibers pass through the Inferior mesenteric ganglion.

 L3 to S5 segments innervate blood vessels of the perineum and inferior extremity.

Special senses:

Visual.

The visual receptors are rods and cones of the retina.

The right optic nerve carries visual input from the temporal half of the right eye and the nasal half of the left eye. The left optic nerve has fibers from the temporal half of the left eye and the nasal half of the right eye. The crossing of nasal fibers is known as the optic chiasma. These fibers then sweep around the midbrain and make a synaptic connection in the lateral geniculate body of the ipsilateral side. The lateral geniculate body is a special section of the lateral dorsal thalamus. The visual sensation reaches the visual cortex by way of the optic radiation. The visual sensation of one side of the visual field is projected to the same side of the visual cortex but contains images from both retinas. This is because there is an overlap of the image when placed close to the nose, each eye captures the image but at a different half of the retina.

Taste sensory pathway.

Receptors:

The tongue, soft palate and throat contain taste buds. These buds are distributed widely but some are more concentrated in one area than the rest. The tip of the tongue contains sweet sensory taste buds and the sides of the tongue contain salt and sour taste buds, the dorsal surface of the tongue for all taste buds, and the back of the tongue for the bitter. The anterior two thirds of the tongue is innervated by the tympanic branch of the 7^th cranial nerve, the Facial nerve. The distal 1/3rd of the tongue and throat by the Glossopharyngeal nerve, the 9th cranial nerve. The epiglottis taste buds are innervated by the Vagus nerve, the 10th cranial nerve. The neurons for the taste sensation of the 7th nerve are located in the Trigeminal nucleus, the neurons for the glossopharyngeal are present in the Petrosal ganglion and vagus sensory neurons are located in the medulla and are known as the Dorsal nucleus of the vagus. The dendrons of these nerves are carried in the tractus solitaries of the vagus. The ascending fibers from these ganglia cross the midline to the opposite side and reach the poster ventral nucleus of the thalamus by way of the Medial lemniscus. The thalamic nuclei relay the taste sensation to the Gustatory cerebral cortex and anterior insular cortex.

These three nerves also carry the general visceral sensation from the tongue, mouth, palate, epiglottis and throat in a separate group of fibers but follow the same path the rest of the way.

Auditory Pathways:

The receptors of sound are hair cells of the organ of Corti located in the cochlea of the middle ear. The 1st order neurons are cochlear neurons carrying the sound impulses to the Superior Olive nucleus of both sides but mostly to the opposite side. The second order neurons of the superior olive pass through the reticular formation of the midbrain and terminate in the lateral geniculate body of the same side. Like the medial geniculate body, the lateral geniculate body is a part of the thalamus and both bodies are located close together. From the lateral geniculate body, the last relay takes the sound sensation to the auditory center in the cerebral cortex. One side of the auditory cortex receives sounds from both ears.

Smell sensation.

The thalamus is not the initial nerve center for the smell.

Receptors: Nasal epithelium contains olfactory sensory cells. The axons pass through the cribriform plate of the ethmoid bone. These neurons relay information with the neurons of the olfactory bulb located above the cribriform plate. The information goes to the ipsilateral primary smell center by the fiber bundle called the olfactory tract. The olfactory tract splits into medial and lateral tracts, and the medial tract carrying the smell sensation terminates in the olfactory cortex. The lateral tact connects with the thalamus, amygdala, and other midbrain nuclei. 

Sexual sensation.

The receptors are locaated in subcuteous tissues of erective organs in bothe sexes, these receptors are similar to Krouse corpuslces. Touch and vibratory senses are received and caries along the lateral spinothalamic tract to the brain. The efferent actions do not depaned on higher connections, the reactions are mostly refex in nature but greatly modified by hypathalmus and cerebarl cortex.

The brain receives a condition of the heart rate. BP, O2 saturation and respiration are continuously monitored by sensory input via the paths described under visceral sensation. The second set of information the brain receives is from the skin and bones and joints via the dorsal ascending column, spinothalamic tracts and spinocerebellar tracts. Integration of all the internal and external sensations and their reflex actions and cerebral motor actions is the basic survival requirement of the species.

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Adrenal Glands.

 

                                                          Adrenal Glands

                                                PKGhatak, MD

A pair of endocrine glands, one sitting on the top of each kidney, separate but closed in by the same kidney capsule and are essential for health and life. Adrenals are also called Suprarenal glands. In adults, the adrenals are small in size, but very vascular, getting the most blood supply per gram of tissue. Like the pituitary gland, the adrenal gland consists of two different endocrine glands - one mesodermal origin endocrine gland, the other neuroectodermal origin endocrine gland. In the developing fetus and newborn adrenal, the size is large in comparison to the whole body. Adrenals are larger than the kidneys at birth and weigh 5 gm. In childhood, the glands start to regress in size but the glands start to grow again at age 4-5 yr., then after the end of the growth period, the size begins to shrink to a mere 4 grams each in adults.

Adrenals lie behind the parietal peritoneum, attached firmly at the back to the pillars of the diaphragm. The right adrenal gland is taller and shaped like a pyramid, and the left one has a wider base and looks like a Napoleon hat; each gland measures about 3 cm x 5 cm x 0.1 cm in height, width and thickness respectively.

The growth and development of adrenal glands are quite distinct in humans and not matched in other mammals except perhaps that of chimpanzees. The fetal adrenals function differently than adult adrenals and in association with the placenta provide estrogen for fetal growth.

Fetal adrenal glands.

Some of the neuroectodermal cells of the neural crest migrate near the dorsal aorta at 6 weeks of gestation and by 9 weeks come close together to form the fetal medulla of the adrenal gland, one on each side of the dorsal aorta, close to the site of developing fetal Adrenal cortex and genitourinary ridge. A layer of cells from the fetal adrenal cortex surrounds the fetal medulla at 8 weeks of gestation and is called the Definitive zone. The neuronal derived cells take up chromium stain and are so named chromaffin cells and these cells remain scattered in small groups in the fetal cortex. The outer layer of cortical cells is in the proliferative stage, whereas the inner cells develop organelles in order to produce cortisone. It is still debated whether the production of cortisol in the early fetal stage is truly independent of adrenal action or under the influence of pituitary ACTH (adrenocorticotropic). At 12 weeks, a new cell layer called the Transitional zone develops in between the layers. Definitive zone cells reduce the production of cortisol and the cells of the transitional zone begin producing Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone sulfate (DHEA-S). DHEA and DHEA-S are converted to Estrogen in the placenta. Estrogen is needed for fetal growth. At 24 weeks, the size of the fetal cortex is reduced in size and the transitional zone is now called zona fasciculata and the outer definitive zone is called the Granulosa zone. The granulosa zone keeps producing cortisone under the influence of ACTH. At birth, the medulla of the adrenal gland is still rudimentary and does not secrete hormones and the cortex has only two zones – a larger granulosa zone and a smaller fasciculata zone.

In newborns, the medulla remains inactive, growth starts at 8 months of age and reaches the maximum at 12 to 18 months.

Hormones of the adult adrenal glands.

The adrenal cortex hormones are called Steroid hormones, majority of adrenal hormones have one hydroxyl group (-OH) bound to the carbon atom in the side chain and are therefore also called Sterols.

Cholesterol is the prime chemical from which all steroids are produced. Cholesterol is obtained from the LDH cholesterol of the blood. If the blood level of LDL is low, LDL cholesterol is synthesized in the adrenal cortex. The first step in steroid synthesis is to cleave the side chain of cholesterol and oxidation to generate Pregnenolone. ACTH influences this initial step. This conversion takes place in mitochondria and is then transported to the endoplasmic reticulum of the cell. The endoplasmic reticulum contains specific enzymes for the production of a specific hormone, specific for a zone of the adrenal cortex.

Zona Glomerulosa.

Pregnenolone is converted to Progesterone then oxidized to 11- Deoxycorticosterone. The next step is 18- Hydroxycorticosterone then the final product is Aldosterone. Aldosterone exists in two forms namely 18-aldehyde form and 11-helical form.

Zona Fasciculata.

Pregnenolone is converted to 17 alfa-Hydoxypregnenolone. The next step is 11-Deoxycortisol by hydroxylation then to 11-Deoxycortisol and the final step is Hydrocortisone and Cortisone.

Zona Reticulosa.

The cells of this zone work differently from other zones. Gonadotropin Releasing Hormone of the Anterior pituitary regulates the production of these sex hormones. There are two releasing hormones - Luteinizing releasing hormone (LHRH)and follicular stimulating releasing hormone (FSRH).

Pregnenolone is converted to 17-alfa-Hydroxypregnenolone; then the next step is Dehydroepiandrosterone. The next product is Androstenedione and the final product is Testosterone. The primary adrenal androgens are dehydroepiandrosterone and androstenedione and a tiny amount of testosterone. The gonads of individuals produce most of the sex hormones, stimulated by the pituitary hormones and reproductive cycle and growth period by way of negative feedback.

Adrenal Medulla.

Hormones produced by the adrenal medulla are important but not essential for life. The medulla is in fact a special structure of the sympathetic nerve ganglion. The hormone is known by the generic name Catecholamines, it can be gotten from other sympathetic nerve ganglions. Catecholamines are Nor-adrenaline and Adrenaline, as the Britishers call them, the universal names are Norepinephrine and Epinephrine. About 80 % of catecholamines are epinephrine and 20 % of the rest are norepinephrine.

The catecholamines are derived from the amino acids  -  Phenylalanine and Tyrosine. Tyrosine is converted to L-Dopa ( Levo-dihydroxyphenylalanine) and the next stage is Dopamine. Then to Norepinephrine to Epinephrine. Epinephrine is stored in the chromaffin cells as granules till it is time to release into the circulation.

Regulatory control of Steroid hormones.

Negative feedback is the common control system for all endocrine glands. Both the hypothalamus and pituitary gland monitor blood levels of adrenal hormones. When the blood level falls, say aldosterone, the hypothalamus releases ACTH Releasing Hormone (ACTHRH) and that results in the production of more aldosterone. As the aldosterone level rises the ACTHRH from the pituitary is turned off. Several other paths for steroid hormone production exist.

Aldosterone.

By the Glomerular Apparatus of the Kidney.

In each kidney, there are about 1 million glomeruli, a tuft of capillaries enclosed by a funnel like structure known as the Bowman capsule. A branch of the renal arteriole feeds the glomerulus with blood and is called the afferent arteriole, and blood exits after filtration by the efferent arteriole. A loop of distal convoluted tubule of a nephron at this site and a group of juxtaglomerular mesangial cells of Lacis (Lacis cells) form the Glomerular apparatus. Special muscle cells of afferent and fewer muscle cells of efferent glomerular arterioles lie in layers like a cuff. The modified epithelial cells of the distal convoluted tubule are tall and have a prominent nucleus known as Macula Densa. Extraglomerular mesangial cells are loose networks of connective tissue cells located around the afferent and efferent arterioles. Macula densa monitors sodium and potassium concentration of the urine. The receptor of BP in the afferent arteriole communicates directly with the juxtaglomerular cells(JG cells), and the JG cells release Renin. Renin converts the angiotensinogen of blood to angiotensin I, which is converted to angiotensin II by ACE (angiotensin converting enzyme). ACE is produced by pulmonary endothelium and endothelium kidneys and also by the epithelium of renal proximal tubules.  Angiotensin II acts on the adrenal cortex to increase aldosterone production and release. The Lacis cells produce selective vasoconstriction or vasodilatation of the arterioles based on the nature of the input. Angiotensin I and angiotensin II are broken down by an enzyme angiotensinase to angiotensin III & IV.

The second path is the sympathetic nervous system. In any stressful situation, the hypothalamus discharges neuronal signals by sympathetic preganglionic fibers to sympathetic ganglions. The postganglionic Beta 1 and Beta 2 nerve fibers carry that signal to the adrenal cortex directly to the chromaffin cells without forming synapses and aldosterone is released in the blood in response.

Glucocorticoids.

Similar systems of sensors for glucocorticoids are present in tissues, and information is relayed to the hypothalamic-pituitary-adrenal axis (H-P-A axis). Release of glucocorticoid hormone results. Cortisol breaks down hepatic glycogen to glucose. Glucose generation from amino acids and fatty acids- commonly called glucogenesis happens. Glucose levels are normalized.

The 2nd pathway is through the sympathetic nervous system via the hypothalamus and via the close relationship with epinephrine and norepinephrine.

Regulation of Sex Hormones of Adrenal Cortex.

Gonadal hormones are the main source of sex hormones. Pituitary FSHRH and LHRH, Growth hormone and adrenocortical DHEA, DHEA-S and Testosterone are integrated by the Hypothalamic-Pituitary axis. Adrenal sex hormones are taken up by the gonads and used as the raw material for gonadal sex hormones production. Gonads also produce DHEA and DHEA-S, the initial steps of LH and FSH production.

This scheme of regulation of hormone production is a simplified version. There are much more intricate relationships between hormones, tissue cytokines, chemokines and the production of hormone carrier proteins by the liver. The role of cytochrome P 450, Cyclic AMP, and other enzymes is too complex for this simple presentation. The cytoskeleton of mitochondria and endoplasmic reticulum, the protein messengers for communication between organelle, have a special role also. Aromatase CYP 19 is essential in the conversion of androgen to estrogen. 

Physiological functions of Adrenal hormones.

Steroid hormones are regulators of the whole body homeostasis. Metabolism of carbohydrates, protein and fatty acids is under control by glucocorticoids to maintain an adequate supply of glucose to the tissues. The new sugar is made from protein and fat (glucogenesis), and sugar is freed from glycogen stores called glycogenolysis. Under the prolonged influence of glucocorticoids, the matrix of bone (made of protein) is thinned out and calcium moves out of bone and bones become brittle (osteoporosis). Excess calcium, magnesium,  and uric acid are excreted in the urine.  Renal calcification and urinary stones are common complications. Aldosterone maintains extracellular volume by controlling Sodium loss by the kidney, excreting potassium and hydrogen ions in exchange for sodium. Corticosteroids have profound effects on the cardiovascular system, musculoskeletal system, and central nervous system. Corticoids are suppressors of acute inflammation/infection. The immune cell and lymphocyte functions are downregulated. The production of antibodies is delayed and downregulated. Fetal growth by steroid hormone and maturation of various systems, specially lungs in pre and postnatal stages, is provided by corticosteroids.

A detailed description can be found elsewhere.

Regulation of Catecholamines of the adrenal medulla.

In any stressful situation, the hypothalamus discharges neuronal signals by sympathetic preganglionic fibers to sympathetic ganglions. The postganglionic Beta 1 and Beta 2 nerve fibers carry that signal directly to the chromaffin cells of the adrenal medulla. Regulation and release depend on local tissue negative feedback in addition to nerve hypothalamic control. Noradrenaline increases vasoconstriction, and BP, acceleration of conduction of cardiac impulses, tachycardia.

Epinephrine dilates blood vessels of muscles, increases blood sugar, and dilates bronchial wall and cardiac output.

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Mycoplasma pneumoniae Pneumonia

                                     Mycoplasma pneumoniae Pneumonia

                                         PKGhatak, MD

 

The bacterial Mycoplasma pneumoniae is more intriguing than the pulmonary diseases it produces in humans. Mycoplasma is the smallest self replicating organism that has the smallest genomes. It is a small bacterium without a cell wall. Phylogenetically Mycoplasma pneumoniae (M. pneumoniae) belongs to Clostridia. The bacterial body is covered by a single layer of membrane (the bacterial body has double layered membrane). The cytoplasm has very few organelles and no limiting membrane. The nucleus is a circular double helix without a nuclear membrane. The nucleus contains only 500 to 1,000 base pairs. M. pneumoniae is dependent on the host for nutrients because of having only a limited number of enzymes and protein manufacturing capacity, The bacteria are pleomorphic mostly short filaments measuring 100 nm (nanometer) X 1000nm exists as a parasite in living organisms, and round or oval forms measuring 300 nm are detected in laboratory grown culture medium. It can change shape because of an absence of a cell wall, and it passes through bacterial filters. It is poorly stained, and requires a special DNA stain, Hoechst stain. It is difficult to observe under an ordinary microscope because of its small size. 

 

 In nature, M. pneumonia lives as a saprophyte and parasite. The infective filamentous form has a harpoon like terminal organelle and is used to attach to the respiratory epithelium, and is able to resist removal by the mucociliary escalator. A protein, P 1, is present on the surface membrane, it performs multiple important functions – it is an adhesion protein to respiratory epithelial cells, P 1 gives the bacteria its virulence, P 1 is antigenic and antibodies are produced against it. Human RBC contains P I/i protein. M. pneumoniae antibodies react with this RBC antigen and produce hemagglutination. Mycoplasma uses the terminal filament for gliding motion in a liquid medium. The bacteria are difficult to grow in the laboratories, require cholesterol and other nutrients, including the newborn calf's serum, to grow. Laboratories nicknamed Mycoplasma “crabgrass” because the bacteria are difficult to detect, easily contaminate lab equipment and especially cell culture lines, and are difficult to get rid of. It can be successfully cultured on a special agar plate and takes about 3 weeks to grow. The colony looks like fried eggs with the sunny side up. 

  

The bacteria multiply by binary fission, and subsequently, the filaments break into coccus forms. The growing bacterial bodies often do not separate completely and appear as branches fungus like and so named as Mycoplasma ( mykes = fungus, plasma = formed). Also has a tender nickname Mollicute. (molli = soft, cute = skin). The nuclear material is passed to the dividing bacteria by a terminal disc like organelle. At times the nuclear separation is incomplete and appears as a multinucleated form. In infection, the bacteria produce H2O2, superoxide radicals and malondialdehyde at the infection site and which are toxic to tissues and resulting in the desquamation of respiratory epithelium. Denuded respiratory epithelium triggers the cough reflex. The cough continues, even if the infection is controlled because the regrowth of surface epithelium takes time to cover the denuded area.

The biochemical peculiarities of Mycoplasma are also colorful, but not entered into because this will be an unnecessary diversion.

The infection is due to person to person transmission via large sized droplets, and the bacteria remain attached to the respiratory epithelium and thus remain infective. The incubation period is 3 weeks. Children under 6 months of age are protected due to maternal antibodies. Children of kindergarten age show significant infection in the winter months. Older children in high school age and junior college age students have the highest infection rate. Repeated infections are a natural order, adults are much less susceptible. Many studies show high antibodies in the adult population confirming the notion that infection is much more common than recognized.

Signs and symptoms of upper respiratory infection due to M. pneumoniae are not anything as spectacular as the colorful bacterial features. However, M. pneumoniae pneumonia has some interesting aspects. M. pneumoniae pneumonia was one of the many causes of Atypical Pneumonia and Community Acquired pneumonia. Beginning in 1930, the atypical pneumonia was called Walking Pneumonia. In 1944, M. pneumoniae pneumonia was named after Dr. Monroe Eaton as Eaton Agent pneumonia. He demonstrated bacterial filter filtrate of infected secretion from animals produces the same disease in susceptible animals (Koch's postulate), later Dr. Eaton successfully grew M. pneumoniae in eggs. Between 1945 and 1955, M. pneumoniae infections were also called Pleurodynia like organism pneumonia. Finally, in 1955 M. pneumoniae was named M. pneumoniae pneumonia. In 1889 Albert Bernhard Frank coined the name Mycoplasma after detecting fungus like organisms in the plant cell cytoplasm. Endemic M. pneumoniae pneumonia appears in cycles of 3 to 7 years. Many students in summer camps, military recruits, adults and children are especially hit hard during epidemics.

The COVID-19 pandemic has educated the general public that the virus can produce deadly diseases from its effects on cytokines, chemokines and immune cells.  Mycoplasma pneumoniae can cause complications by all these mechanisms. Mycoplasma pneumoniae prefers to be a parasite and produces locally tissue damage from toxins. Symptoms are persistent cough, increased respiratory discharge, low grade fever and headaches. Pneumonia when it develops is patchy, interstitial, sub-segmental and usually peribranchial. A small amount of pleural effusion may also occur. In x-rays, pneumonia appears more extensive than clinically suspected.

At about 7 days after infection, the body begins generating IgM antibodies. Both IgG and IgM antibodies are produced. IgM antibodies are short lived and their presence indicates a recent infection. IgG-complement-fixing antibodies used to be the main laboratory test for the detection of a recent M. pneumoniae infection. The IgG antibodies can persist for up to 4 years. A rising titer of 4 times to 64 times is used as the diagnostic criteria by some labs.

In the first few days of respiratory infection, antibodies produced are cold sensitive, and cause hemagglutination at a low temperature (0 degree C), but appear only in about 50% of cases and last only a week. Moreover, other infections/ diseases can produce cold agglutinins also. Fortunately, all these tests are abandoned or in the process of being abandoned and should be considered as relics of the past. The direct detection of Mycoplasma antigen by DNA probe, bacterial DNA detection by nuclear amplification, PCR and various other modified PCR test technologies have replaced serological tests for the diagnosis of acute M. pneumoniae pneumonia. But serology tests have their place in research. 

Complications.

The incidence of extrapulmonary complications is about 25 %. Most commonly seen in skin, manifested as erythema multiforme. Steven Johnson syndrome rarely happens. Complications involving the GI tract, musculoskeletal and other systems are seen but are minor and self-limiting. More serious complications are Hematological and neurological.

Hemolytic anemia.

Hemolytic anemia is a serious complication of Mycoplasma infection. Antibodies produced against the P1 surface antigen of Mycoplasma pneumoniae cross react with RBC I antigen and produce hemolysis in cold temperatures. This is called cold hemagglutination. This is not however unique to Mycoplasma. This is also seen in Infectious mononucleosis, Cytomegalovirus infection, SARS-CoV2 viral infection, and Aggressive B-cell lymphoma.

Hemophagocytic lymphohistiocytosis (HLH) syndrome.

It is rare but important because this is a potentially fatal disease. Macrophages become cannibalistic and start to devour RBC, Platelets, WBC and the precursor cells in the bone marrow. This transformation of macrophages is brought about by cytokines. Enlarged spleen, jaundice and pancytopenia are distinctive features. An increase in acute phase reactants in serum and in the peripheral smears erythrophagocytosis in macrophages are seen. In delayed diagnosis the outcome is bad.

Neurological complication.

The neurological complications are many. But fortunately, only about 1 to 7 % of cases develop neurological complications. The neurological complications are of two categories- early and late. 

 Early. Aseptic meningitis is due to M. pneumoniae invasion of the CNS (central nervous system). But controversies of the pathogenesis of neurological diseases continue. Those who support direct invasion mention that the blood vessels develop endothelial cellular gaps making entry of bacteria to the meninges possible. The DNA of M. pneumoniae is detected in the cerebrospinal fluid in 10 out of 17 cases in one series, but only in 1 to 10 % of cases of other CNS complications.

Late.  Transverse myelitis and thrombotic lesions of CNS are due to microvascular platelet thrombi. Gillian-Barrie syndrome, Polyradiculitis are considered autoimmune manifestations. It is known that M. pneumoniae surface glycolipid is antigenic and antibodies cross-react with the myelin of the nerve sheath or to the neurons. Other CNS diseases are encephalitis and meningoencephalitis. All these late neurological complications are due to Cytokines induced or autoimmune diseases.

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Respiratory Failure. (Simplified version of Pathophysiology)

                                                    Respiratory Failure

                                            PKGhatak, MD

 Lungs are vital for survival. Disease, congenital abnormality, advanced age, or environmental condition produce changes in the structural and functional state of the lung to a degree that sustaining life becomes precarious and the condition is called respiratory insufficiency. When respiratory insufficiency, producing a low partial pressure of oxygen of arterial blood at or below PaO2 50 mmHg or partial pressure of arterial blood carbon dioxide PaCO2 of 50 mmHg or above, usually both at the same time, is known as respiratory failure.

Lack of Oxygen: It is widely understood that oxygen is essential for cellular respiration and normal bodily functions. Brain cells are particularly vulnerable to low O2, next are the heart, kidneys, and liver.

Why CO2 accumulation is bad: CO2, when dissolved in the blood, forms an organic acid CO2 + H2O = H2CO3. The H2CO3 immediately breaks down to  H2CO3 = H +HCO3. [H+] enters the cells (RBC) and K[+] is pushed out from the RBC into plasma and excreted in urine; the [HCO3-] combines with Na[+] inside the RBC and forms Na + HCO3 = NaHCO3. NaHCO3 reenters the plasma of blood. The enzyme carbonic anhydrase helps this reaction both ways. By this action, the blood manages to keep the pH at an optimal 7.4. When this Bicarbonate buffer system is overwhelmed by the rapid accumulation of CO2, two other blood buffers, namely Phosphate buffer and Protein buffer, try to maintain pH. The more CO2 accumulates, the pH becomes lower and lower, 7.3 ->  7.2->  7.1. And at this acid pH most cells function poorly and soon will die if the condition persists.

Effects of high CO2 in alveolar O2: Air entering the lung becomes fully saturated with water vapor. That means air pressure is 760-47 = 713 mmHg. The partial pressure of alveolar air O2, PAO2 is 20% of 713 = 160 mmHg. O2 is diluted further by CO2, as CO2 enters the alveoli from blood. Normal PaCO2 is 40 mm Hg. The O2 pressure now is 160 - 40 = 120 mmHg and arterial PaO2 is 110 mmHg (120 to 110) happens during the transition called A-a gradient. Oxygen saturation at PaO2 110 mmHg is 100 %.

In acute respiratory failure, assume that the CO2 is 70 mmHg, and the PAO2 will be 160-70=90 mmHg. At PAO2 90 mmHg arterial blood oxygen saturation is 87 %. That is hypoxemia. (the normal O2 saturation of arterial blood is 93 to 100 %).

 A simplified version of the lung is like a bellow seen in a blacksmith workshop. Lungs expand, taking in the fresh air and blowing out stale air by breathing out. Lungs are encased in an elastic box made up of vertebrae, ribs, intercostal and abdominal wall muscles and a muscular diaphragm. The respiratory center is situated in the hindbrain (actually three in number, inspiratory, expiratory in the medulla and pneumotactic center in the pons). The aortic body monitors O2, CO2 and pH of the blood and the Carotid bodies monitor O2. The motor nerve for the diaphragm is the phrenic nerve, the neurons are situated in the cervical 4^th and a few in C3 and C5 spinal cord segments and spinal motor nerves for the respiratory muscles are supplied by the thoracic T1 to T12 and lumbar L2 segments of the spinal cord.

The heart pumps blood to the lung alveoli to pick up oxygen before the oxygen can be distributed to all living tissues of the body and at the same time, the accumulated waste product of energy generation is carbon dioxide and which must to eliminated. Like a heat exchanger, the lung capillaries exchange CO2 of blood for O2 of the air in the alveoli. The transfer of gases is governed by laws of differential pressure gradient and solubility coefficient. O2 has a high affinity for hemoglobin and CO2 is forced out by an enzyme, carbonic anhydrase.

Like a well lubricated machine, the airways of the lungs are kept moist and free of debris by mucus, and the airspace inside of the alveoli is kept open by surfactant. Any malfunction, of the above components or a combination of some of them, will cause respiratory insufficiency that may eventually lead to respiratory failure. Respiratory failure may develop suddenly, as in strangulation or drowning, called Acute Respiratory failure or after a prolonged period of an illness called Chronic Respiratory Failure as seen in pulmonary emphysema or kyphoscoliosis.

 Common causes of Respiratory Insufficiency that may lead to Respiratory Failure.

A. Chest wall: Multiple broken rib fractures and fracture of the sternum produce a frail chest wall limiting patients' ability to inhale. Pleurisy, herpes zoster and other painful chest wall pain can produce respiratory insufficiency. Severe spinal deformities, either congenital or acquired, usually lead to respiratory failure.

B. Reduced Space in the chest cavity: Massive pleural effusion, hemorrhagic effusion, empyema makes less space available for the lungs to expand.

C. Space occupying lesions: Thymoma, Lymphoma.

D. Loss of Lung volume: Pneumonectomy, pulmonary emphysema with bullous formation, pneumothorax, extensive cavitary disease of the lung.

E. Consolidation of lungs: Pneumonia specially in the elderly in nursing homes. If pneumonia is bilateral, usually viral pneumonia like COVID, the alveolar surface area available for gas exchange becomes limited, accumulated secretion in the airways prevents normal air turnover in the lungs. That results in low O2 and accumulation of CO2 respectively.

F. Airway obstruction: Obstruction of the trachea by a foreign body, tumors, hemorrhage, large peritonsillar abscess.

G. Airway disease:  COPD, Asthma, cancers of main bronchus and trachea. These conditions produce limitations of air entry and exit in the lungs.

H. External pressure on major airways: Strangulation, invasive carcinoma of the thyroid gland.

I. Diseases of mucus and mucus clearance mechanism.: Cystic fibrosis, ciliary dyskinesia, bronchiectasis. Microorganisms flourish under those conditions, producing pneumonia and destruction of lung tissues.

J. Reduced capillary bed: Emphysema, recurrent pulmonary emboli, micro-platelet thrombi in covid, ATTP. Pulmonary fibrosis. These conditions prune surface areas of alveoli and capillaries making O2 transfer difficult.

K. Ventilation - Circulation Mismatch: a segment of the lung may have limitations of air entry due to airway disease or produce reduced blood circulation due to emboli, consolidation, or atelectasis. That will lead to wasted ventilation or transfer of O2.

L. Liquid filled alveolar space: Congestive heart failure, pulmonary edema, intrapulmonary hemorrhage, drowning. Air from the alveoli is pushed out by the liquids.

 M. Pump failure: Acute left ventricular failure, massive pericardial effusion, or traumatic pericardial effusion.

 N. Diseases of the nerves supplying respiratory muscles: Poliomyelitis, Guillain-Barré syndrome, ascending polyneuritis. Succinylcholine intentional use. Botulinum poisoning. Paralysis of muscles that move the chest wall in and out results in ventilatory failure.

 O. Central nervous diseases: Respiratory centers are robust and keep functioning as long as the blood supply to the respiratory center remains intact. Herniation of the brain from pressure following a massive brain hemorrhage, or removal of CSF by a spinal tap in inappropriate conditions. Opioid overdose.

An abnormal condition of alveolar capillaries, severe iron deficient anemia, emboli in the lung and pulmonary fibrosis, and loss of surface area of alveoli produce low arterial oxygen, whereas, under the same circumstances, CO2 easily crosses from blood to alveolar air. That is because before any gas has to combine with hemoglobin or leave hemoglobin for the air in alveoli, that gas has to dissolve in the blood first. And CO2 is 160 times more soluble in blood than O2. The only way CO2 can accumulate in blood if the exchange of air in the alveoli lags behind. That is known as Ventilatory Failure. When a low O2 in arterial blood is present, it is called Hypoxemia.

Respiratory Failure.

The common causes of Chronic Respiratory Failures are - advanced COPD, Pneumonia in chronic renal, hepatic, or cardiac failure and pneumonia in the elderly in debilitated conditions. In patients surviving more than 3 days with acute respiratory failure, the kidneys start generating bicarbonate and turn acute to chronic respiratory failure, into chronic respiratory failure. 

The common cause of Acute Respiratory Failure is – COPD with pneumonia, Narcotic overdose, sudden myocardial infarction, cardiac arrest and massive hemorrhage, and pulmonary edema.

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Near Drowning

                                                            Near Drowning

                                                   PKGhatak, MD

Some drowning victims are rescued in time and revived by cardiopulmonary resuscitation (CPR). They are designated as Near Drowning.

  The World Health Organization reported 236,000 drowning deaths in 2019. Drowning is the 3rd leading cause of accidental death in the world. Many believe that the number is actually over 500,000 because of a lack of information from less developed countries.

  Submersion is when the upper airways are underneath the liquid, cutting off the air supply. Immersion is when the body is underneath the liquid and the upper airways are above the liquid, maintaining an open path for air to reach the lungs. Both submersion and immersion generate several changes in the body, some are reflexes, others are biochemical and pathophysiological. Biological changes due to submersion are discussed here.

 Near Drowning may take place in warm water or cold water. The effects of water temperature have profound effects on the body.

 Diving Reflex.

 In submersion, the air is cut off, which triggers a reflex attempt to breathe and as a result, a small amount of water enters the airway. This produces laryngospasm and the glottis is blocked, and further water entry into the lungs is prevented. The breath holding continues as long as the face is completely underwater. Subsequent events differ between warm water submersion and cold water submersion.

 This reflex action involves the following cranial nerves: Trigeminal, Vagus, and Glossopharyngeal. Some fibers of the vagus nerve also supply the heart, and Sympathetic alpha fibers similarly innervate the heart.

  Warm water submersion produces vasodilatation and hypotension, which result in sinus tachycardia and tachypnea.

 Coldwater submersion produces vasoconstriction and bradycardia, increases peripheral vascular resistance, reduces blood flow to muscles, resulting in low oxygen and high carbon dioxide blood levels, causing proportionally increased blood flow to the brain.

 The respiratory center is situated in the brain stem. It produces breath withholding as long as submersion continues. The aortic and carotid bodies monitor hypoxia and produce vasoconstriction by alpha1 sympathetic nerves.

 Continued submersion produces cerebral anoxia, in spite of increased blood flow, and anoxia in vital neuronal centers results in the relaxation of muscles of the larynx and glottis, followed by water entry into the stomach and to the lungs. Underwater seizures may take place. Anorexic cerebral function loss can be extensive; some are reversible, others are not.

  Other injuries and effects of water submersion.

 Shallow water diving can produce fractures of cervical vertebrae, skull, and ribs. Weeds and other vegetation may enter the mouth and throat. Fresh water in the lung alveoli washes away surfactant and leads to atelectasis. Saltwater pulls water from capillaries due to higher osmotic pressure and then destroys the surfactant. Atelectasis causes a mismatch of ventilation and circulation and increases intrapulmonary shunt. In general, about 100 to 200 ml of water enters the lungs. That much water does not increase blood volume or electrolyte imbalance as previously thought, nor does significant hemolysis take place.

 Hypothermia is common. The core body temperature depends on the water temperature and duration of submersion. Effects on the heart in cold water submersion are sinus bradycardia, A-V nodal block, atrial tachycardia, and atrial fibrillation, but ventricular arrhythmias are less common. The cardiac arrest can happen.

 Bacteria, viruses, and parasites are usually found in lakes and tanks. Various infections should be anticipated. Aspiration of gastric content happens during or after resuscitation and produces anaerobic pneumonia.

 Non-Cardiac Pulmonary Edema: 

In saltwater drowning, hypertonic water draws water out of pulmonary capillaries and disrupts the endothelial cells of the alveolar capillaries. Plasma enters the alveolar space and pulmonary edema develops. The amount of seawater of 3 to 4 ml /Kg body weight can produce pulmonary edema,

 Cardiac collapse may develop after the initial rescue and revived by cardiopulmonary resuscitation (CPR). In deep water drowning, water pressure around the thorax increases cardiac output. CPR increases cardiac output further, causing cardiovascular collapse.

 CPR in Near Drowning is different from CPR for heart attack victims. The primary goal of CRP in Near Drowning is to correct hypoxemia as fast as possible and then correct other abnormalities, deliberately paced and not so fast, be vigilant and monitor the victim continuously. 

 The Red Cross publicizes CPR instructions for the general public and provides advanced training for first responders. CPR should be started as soon as the victim is brought to shallow water or on land by the rescuer and then call for additional help.

 No attempt should be made to drain water from the stomach. Those maneuvers only promote aspiration. Use of the defibrillator should be delayed because the carotid pulse is difficult to palpate on the cold and clammy skin of the victims. Without an ECG (EKG) confirmation, no attempt should be made to diagnose asystole or VF (ventricular fibrillation). Moreover, the chilled heart does not respond properly to external electric shocks applied.  Wet clothing should be removed and the body should be wrapped in a warm blanket.

 Warming the victim should only be done in hospitals equipped with extracorporeal heating and extrapulmonary membrane oxygenation facilities.

 All Near Drowning victims should be admitted to the hospital. Correcting hypoxia, hypercarbia, and acidosis in the presence of cerebral anoxia calls for Pulmonary / Critical care specialists. One should not use PEEP (positive end-expiratory pressure) without the input of PCWP (pulmonary capillary wedge pressure). Significant cerebral dysfunctions should be anticipated and addressed promptly and may require rehabilitation services upon discharge. Convulsion, hypoxia. Cerebral anoxia, hypotension, cardiac arrhythmia, pneumonia, and noncardiac pulmonary edema should be treated properly.

edited: June 2025.

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Spit Sputum Phlegm

                                                                 Sputum

                                                    PKGhatak, MD

Sputum is another name for spit. The word sputum is derived from Latin Spuere. The aristocratic name of spit is Phlegm. That word is derived from the Greek word Phlegein. The old French language modified it to Flume, the old English named it Fleem and finally modern English is Phlegm.

In India Phlegm is the answer to a trivia question - what is that substance that the poor discard it indiscriminately and the rich carefully save it in between the folds of monogrammed handkerchief and tuck it carefully in their pocket/purse.

When all the humor is removed, the sputum is made up of mostly water, a bit of mucin, and 1 % salt. Mucin is secreted by the Goblet cells of the respiratory tract. Chemically mucin is a polymer of glycoproteins. Mucin has a complex structure. The core is composed of structurally strong protein molecules composed of amino acids serine, proline, and threonine and the core protein is bonded to various oligosaccharides by O-glycosidic linkages. Then the pattern is repeated several times, the sequence of which is highly variable in length and amino acid composition.  90 % of mucin is carbohydrate. Mucin is highly hygroscopic and keeps particulate matter and microorganisms wrapped up tightly. In addition, the sputum contains a few shredded epithelial cells, WBCs, lysosomes, IgA antibodies, lactoferrin and usual respiratory and oral flora.

For the medical profession, the sputum is nothing to sneer about. Whatever is responsible for a disease of the lung, sooner or later it has to come out dead or alive, with the sputum. Naturally, the sputum examination provides a direct clue of an illness and is also used to monitor the progress of the disease.

Let's look at the sputum.

Generally, sputum is collected in the morning. The patient is instructed to rinse their mouth with water, then cough vigorously for several minutes and collect sputum in a sterile container provided by the lab. The sputum should contain secretion from deep inside the lung and not saliva. If the sample contains only a few WBCs and more than 20 epithelial cells per low power field, the lab rejects the specimen and marks "inadequate sample" and requests resubmission. In some lung diseases, the patient can hardly raise the sputum. To facilitate sputum collection, inhalation of nebulized 3% saline is used, at times assisted by chest percussion with cupped hands. If that fails, the samples are obtained at a bronchoscopic examination.

Sputum is examined for color, smell, amount, consistency, frothiness, foaminess, cellular debris, crystals, malignant cells, microorganisms, parasites, fungal spores, and filaments, amoeba. Then smears are made, properly stained and examined under a microscope to identify microorganisms.  Cultures are planted on proper media for bacteria and fungi. Special methods are used for malignant cells to obtain a better yield. Sputum is handled separately for tuberculosis. Alkaline digestion of the gastric aspirate sample was then centrifuged. The sediment is used for culture. Sputum from gastric content is another source in patients who are unable to raise sputum as in young children and unconscious patients.

Color of sputum and its significance:

The primary reason for sputum examination is an infection of the lungs, other important reasons are hemoptysis and lung cancer. Bacterial pneumonia produces thick yellow-green sputum; the green color is due to the presence of myeloperoxidase and the yellow color is from degenerated neutrophils.  Bloody sputum is due to hemorrhage in the lung. (see the section on hemoptysis blog).  Red jelly like sputum is from Klebsiella pneumonia.  Blood streaking sputum is generally due to cancer of the lung. Rusty color is from Pneumococcal pneumonia.  The brown color is from Cancer of the lung and tuberculosis.  Grayish white is from dehydration.  Pink frothy sputum is due to acute pulmonary edema.  White, opaque and scanty sputum is from asthma.  Green sputum is from Pseudomonas pneumonia. Black sputum is common in coal miners' pneumoconiosis, Aspergillus niger infection.   

Smell of sputum:

The putrid smell is associated with the breakdown of tissues from bacterial enzymes releasing gases containing hydrogen sulfide, aromatic compounds, aldehydes, and ketones.   Foul smelling sputum is from anaerobic bacterial infection, usually from a lung abscess, however, infection by an anaerobe from the gum to the lung generates a foul odor.   The wet fur smell is from Hemophilus influenza pneumonia.   The acrid smell from Bacteroides fragilis.  The burnt chocolate smell from Proteus mirabilis pneumonia. Some other Proteus species can produce an odor of rotten fish.  Dirty sneaker smell from Citrobacter.  The fecal odor from Pepto streptococcal infection. Pneumonia caused by Bacteroides, Proteus, and Peptostreptococcal is rare and seen in immunocompromised patients.   The buttery smell is from Streptococcal viridans infection.  The musty odor from Streptomyces.  The sweet fruity odor from Pseudomonas aeruginosa pneumonia.

Amount of sputum:

COPD patients with pneumonia can produce 100 to 200 ml sputum. Bronchiectasis, in general, produces over 150 ml of sputum a day. Patients with acute left ventricular failure can produce over 150ml of pink frothy sputum. In asthma and in pure pulmonary emphysema only a small amount of sputum is raised.

Consistency:

Watery sputum is just saliva. In a single nodular lesion due to suspected cancer or tuberculosis, no sputum may be generated and collected specimens are watery. Thick yellow sputum indicates bacterial pneumonia, and viral pneumonia can produce light yellow green sputum. Foamy sputum is from air bubbles trapped in the sputum, commonly seen in COPD. White frothy or pink frothy sputum in pulmonary edema. Thick sticky sputum is from Cystic fibrosis. Chocolate mousse sputum from ruptured amoebic liver abscess through the lung.

Parasites in sputum:

Ascaris lumbricoidis is usually coughed up alive and found wiggling in a sputum cup.

Strongyloides stercorales larvae, and hookworm larvae are also seen in heavy infestations.

Parasitic ova:  Paragonimus westernanii eggs are a common finding in that fluke infection of the lung. 

 Schistosoma eggs are occasionally coughed up in liver cirrhosis when a hepatopulmonary shunt is formed.

Entamoeba histolytica in sputum is seen in cases where amoeba invades the lung from the liver through adhesion.

Fungal Filaments:

Pneumonia from Aspergillus fumigatus, Candida albicans, Actinomycetes israeli, Nocardia (previously grouped with bacteria Actinomyces) cases, sputum contains fungal filaments.

Fungal yeast form: All dimorphic fungi are recovered in the sputum of disseminated infection. These fungi are Histoplasma capsulatum, Blastomycoses brazilianus, Coccidioides immitis, Sporothrix schenkii.

Fungal spores are seen in Candida, Cryptococcus, and Pneumocystis jirovecii lung infection.

Crystal in sputum: Calcium oxalate crystals are a hallmark in Aspergillus pulmonary infiltrative disease. The byproduct of growing Aspergillus is oxalic acid, which combines with serum calcium to form crystals. Charcot Leyden crystals are formed from degenerated eosinophils seen in asthmatics. Curchmann's spirals are coiled basophilic mucinous fibrils seen also in asthmatics.

Foreign Bodies:  

Foreign bodies are seen in coughed up sputum due to aspiration of food and drinks. Vegetable matter is often removed by bronchoscopy. Two groups are most susceptible to aspiration - young children and nursing home patients with bulbar palsy, stroke with dysphagia, and neurogenerative diseases. Uncommon objects found in the sputum are - broken toy pieces, magnets, glass beads, buttons, pennies, pins, small nails, partial dentures, small fruit seeds, decayed teeth, surgical sutures, hard candies, and others.

Distinctive features of Cystic fibrosis sputum are very sticky, green, and fruity in smell. In the case of bronchiectasis, the collected sputum separates into three layers, the bottom layer is the necrotic tissues, the clear middle layer and the top foamy layer.

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Noncardiac Pulmonary Edema.

                                      Noncardiac pulmonary edema (NCPE)

                                       PKGhatak, MD

Pulmonary Edema is an acute illness due to fluid accumulation in inter-alveolar connective tissues and in the alveolar spaces of the lung. The most common cause of acute pulmonary edema is Left Ventricular failure from a massive left ventricular infarction. However, pulmonary edema also happens from other than an acute left ventricular failure. These conditions are called Noncardiac Pulmonary Edema (NCPE)

NCPE: 

The basic mechanism of NCPE is alveolar capillary leak. There are various reasons or conditions leading to capillary leak producing pulmonary edema. The characteristic features of NCPE are that the pulmonary capillary wedge pressure (PCWP) and PAP (pulmonary artery pressure) remain normal or low, and the ratio of protein in pulmonary edema fluid and serum protein is over 0.7.

Common causes of NCPE.

 1.Covid-19 induced cytokine storm. 2. Adult respiratory distress syndrome (ARDS) resulting from gastric aspiration, pancreatitis, sepsis, open chest cardiac surgery, chest trauma, drug overdose. 3. Pulmonary embolism. 4. Neurogenic - seizures, Brain surgery, subarachnoid hemorrhage, meningitis. 5. Narcotic overdose. 6. High altitude pulmonary edema (HAPE). 6. Toxic gas inhalation, Thermal injury to lungs in open flame fire incidences. 7. Salicylate intoxication. 8. Transfusion related acute lung injury (TRALI) 8. Near drowning. 

Other causes of NCPE: - Reperfusion and re-expansion pulmonary edema. Fluid overload. Post obstructive. Following the lung transplant. Drug reaction and hypersensitivity reaction. Exercise induced. Air embolism.

Diagnosis.

When a patient presents with acute respiratory distress, coughing up pink frothy sputum, extreme anxiety and altered consciousness with signs of overworked muscles of respiration, central cyanosis, moist rales on auscultation, various degrees of shock, the diagnosis of Pulmonary edema is not difficult. Low oxygen saturation in digital oximetry, X-ray shows no cardiac enlargement, no dilatation of major branches of the pulmonary artery. Bilateral peripheral symmetrical " batwing" opacities, the diagnosis is made. ECG will show no right/left ventricular strain, hypertrophy or major arrhythmia. Rarely fluid/serum protein ratio or PCWP are required for the diagnosis of NCPE. The history of the illness will clearly point toward the cause.

The newer Ultrasound devices can detect septal edema, and thickened minor fissures in NCPE are reported as B lines. The B lines are artifacts generated by reverberations of sound waves and appear generally in a group of three, separated by 7 mm one group from the next group.

Treatment.

Immediate oxygen therapy is instituted by the first responders, then proper oxygenation has maintained by any means, and when respiratory failure is also present noninvasive or invasive mechanical ventilation is instituted.

Other modalities of therapy vary according to the etiology of NCPE.

Prognosis. NCPE outcome is much better than cardiac pulmonary edema.

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Eosinophil and Acute Eosinophilic Pneumonia.

                                        Eosinophil and Eosinophilic Pneumonia

                                             PKGhatak, MD

Eosinophils are white blood cells (WBCs), belong to cellular immunity and are called immunocytes. Eosinophils are strikingly different from the other WBCs.

The cytoplasm of the eosinophil contains many granules, stained red or pink with an acidic dye, Eosin. The name eosinophil means - love eosin. The nucleus of the cell is bi-lobed. The granules contain preformed enzymes, lysosomes, cytokines, prostaglandins, thromboxane. The cells also supply NO, O, H2O2, and OH groups. Cells exhibit amoeboid movement and phagocytic activities. The surface of cells contains various receptors, namely cytokine receptors, active receptors, lipid mediated receptors, pattern recognition receptors, FC fraction immunoglobulin receptors, and adhesion receptors.

In health, the eosinophils are present in the thymus gland, spleen, lymph nodes, entire GI tract with the sole exception of the esophagus, and in the bone marrow and peripheral blood. Eosinophils migrate to tissues when summoned by Interleukin IL-3 and IL-5. They move out of blood vessels by Brownian movement and attach to cells and tissue by adhesion receptors and then release stored chemicals. The chemical paralyzes parasites, stimulates phagocytosis by macrophages, may produce damage to tissues, and participate in inflammation, repair and remodeling and regeneration of organs/ tissues.

In the peripheral blood, the eosinophils count is 2 to 8 % of the total WBC. The actual number is between 500 to 800 per mcL. The life span of eosinophil in the peripheral blood is 2 to 4 days and in the tissues 14 days or longer by the action of interleukin.

Eosinophils produce airway constriction by histamine release from mast cells, increase mucus secretion from goblet cells, and promote the proliferation of intercellular matrix by TGFB.

When the eosinophil count increases over 800 /mcL the condition is known as eosinophilia. In chronic eosinophilic syndrome, the count is over 1,500 /mcL. In chronic eosinophilic leukemia, the count is over 100, 000 /mcL.

Eosinophils are very active in parasitic infestation, allergy, asthma, drug induced allergy, and cancers. There are some special diseases that arise from eosinophil dysfunctions and one of them is Acute eosinophilic pneumonia. 

Acute Eosinophilic Pneumonia:

Acute eosinophilic pneumonia is a rare disease but a serious illness. The illness develops most frequently in young males in 20 to 35 years. of age who are trying to start smoking cigarettes for the first time or have taken up smoking again after a brief period of quitting. Pneumonia once starts rapidly spreads to both lungs and in 4 to 7 days becomes quite extensive. The distinctive features of this rapidly spreading pneumonia are progressive shortness of breath and quick onset of respiratory failure. Blood count shows no increase in eosinophil count.

The pathological picture is of interstitial pneumonia with extensive infiltration of eosinophils. Other features are rapid loss of weight, night sweats, cough and fever.

The cause of the illness is unknown. Various theories are advanced but none are convincing. And no hereditary predisposition is known.

Clinical signs are typical interstitial pneumonia. Diagnosis is based solely on finding a large percentage of eosinophils in the bronchial lavage fluid obtained at the time of bronchoscopy, and/or demonstrating massive eosinophil infiltration of lung parenchyma in the biopsy specimens.

Treatment.

A marked drop in O2 saturation may develop at any time, so monitoring of patients in the ICU is essential and prompt correction of O2 deficiency is needed. Respiratory failure is treated with non-invasive ventilation or intubation and mechanical ventilation. High dose IV steroid shows quick response; 3 to 5 days later IV steroid is switched to the oral route and gradually completely withdrawn. Once recovered from an acute illness, there is no recurrence of pneumonia and the prognosis is excellent.

Acute eosinophilic pneumonia requires to be differentiated from Chronic eosinophilic pneumonia, Churg-Strauss syndrome, Loffler's syndrome and Tropical pulmonary eosinophilia.

Chronic eosinophilic pneumonia is not a disease of the young, the peak incidence is in the 5th decade and both sexes are equally affected. It is chronic and recurrent in nature and often accompanies asthma. Pneumonia does not lead to respiratory failure. Blood count shows high eosinophils in the peripheral blood in contrast to acute eosinophilic pneumonia.

Churg-Struss syndrome is a multisystem eosinophilic vasculitis with granuloma formation. Asthma is often an underlying condition, and blood eosinophil count is high. 50% of cases show the presence of c-ANCA (ANCA= antineutrophilic cytoplasmic antibody).

Loffler's syndrome is recurrent asthmatic episodes due to infiltration of the lungs by eosinophils resulting from larval migration through the lungs. The larvae are Ascaris lumbricoides and also larvae of other parasites. Blood eosinophil count is high.

Tropical eosinophilia is a prevalent disease in coastal areas in India and the Indian subcontinent. Eosinophil count is generally over 3,000 /mcL, serum IgE levels over 1,000 units and a positive filaria antigen test. Symptoms of wheezing, cough and asthma like attacks coincide with the periodic release of microfilaria into the blood by adult filaria worms residing in lymph nodes. The pathological picture varies according to the duration of the disease from simple pulmonary eosinophil infiltrates to pulmonary fibrosis.

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Pulmonary Arterial Hypertension - Basic Science and Rational of Therapeutics.

                                                Pulmonary Hypertension

                                            PKGhatak, MD

There are two separate circulatory systems - the greater and lesser circulatory systems. The greater system consists of the left atrium, left ventricle, aorta and its extensive branches to supply nutrients and oxygen to every living cell. This system is also called the Systemic Circulatory System. The lesser circulatory system consists of the right atrium, right ventricle and pulmonary artery and its branches to the lung alveoli. This is called the Pulmonary Circulatory system and this system delivers carbon dioxide to the lungs for elimination by ventilation and carries fully saturated oxygenated blood to the left atrium.

The circulating blood in the arterial tree exerts lateral pressure on the wall of the blood vessels and must overcome resistive wall pressure to propel forward. This wall resistance is called peripheral vascular resistance. This vascular resistance is commonly called Blood pressure - should be correctly called Systemic BP and Pulmonary BP.

Systemic blood pressure is easily measured on the arm by a BP instrument, either a mercury manometer or indirectly by a digital BP instrument which is properly calibrated. To measure the pulmonary arterial BP, a catheter must be inserted in the subclavian vein or femoral vein, then advanced to the right atrium, right ventricle, to the Pulmonary artery and then record the pulmonary arterial pressure. This invasive procedure is not practical for clinical practice.

In recent years, the Doppler Echocardiography and supplemented by 12 lead ECG, has to a greater extent, made monitoring pulmonary arterial BP much simpler and practical. The normal systemic BP is 120/80mm Hg and the normal pulmonary arterial BP is 20/10 mmHg.

These two circulatory systems are interconnected. The venous return of the systemic circulation comes to the right atrium via the superior vena cava and inferior vena cava. The venous blood from pulmonary circulation returns to the left atrium by pulmonary veins. This means diseases/ conditions of one, eventually, involve the other system.

Two other numbers are important in clinical practice - Mean Arterial Pressure (MAP) and Pulmonary Capillary Wedge Pressure (PCWR). MAP is the tissue perfusion pressure. The PCWR is a good approximation of the left atrial pressure.

MAP is calculated: MAP = (systolic BP /3) + (2x diastolic BP / 3).

The pulmonary artery/capillary wedge pressure is measured by a Swan Ganz catheter. This is obtained by advancing the catheter tip to the distant pulmonary arteriole and then inflating a small balloon to prevent pulmonary artery blood flow temporarily. The normal PCWR is 8 to 10 mm Hg.

In critically ill patients, pulmonary vascular resistance (PVR) is measured several times a day. PVR guides in adjusting fluids and vasopressor therapy, adjustment of ventilator settings, among other therapies. Pulmonary vascular resistance is calculated at the bedside from Swan Ganz catheter values.  Pulmonary artery pressure(PAP), pulmonary artery wedge pressure (PCWP) and cardiac output (CO) are necessary to calculate the PVR. 

 PVR =(PAP - PCWR) / CO.

In clinical medicine, PVR is expressed by using the Wood Unit.  Cardiac output is determined by thermodilution using cold saline. Woods unit is calculated using formula PVR = 80 x (PAP - PCWP) / CO. The normal PVR is 1 wood unit, a 3 Wood Unit is Pulmonary Arterial Hypertension or simply Pulmonary Hypertension.  In PAH the mean pulmonary BP is over 25 mm Hg, and PCWP is over 15mm Hg.

In physics, the Hagen-Poiseuille equation is used to determine the resistance of the tube using a formula R= 8 x L. n. r>4 (>4=raise to the power 4). Where R stands for resistance, L for the length of the tube, n for the viscosity of the fluid, and r for the radius of the tube.  In clinical medicine, the same equation remains valid. Variation of these parameters leads to pulmonary hypertension.

Pathological changes leading to hypertension:

Even a casual look at the Hagen-Poiseuille equation points out that a change in the lumen of the artery leads to a marked increase in BP. Regardless of different causes of PAH, there are common pathological changes in the pulmonary arterioles that produce narrowing of the arteriole lumen, increase PVR, hypertension and consequently right ventricular hypertrophy and cardiac failure and death. Pathological lesions are characterized by enhanced arteriolar smooth muscle contractility, dysfunctional arteriole due to aberrant remodeling of both endothelium and muscle layers and finally the microthrombi in capillaries.

Several of the following pathways are known to alter and result in pulmonary hypertension:

Nitrous oxide (NO) + soluble Guanylate cyclase pathway. The endothelial cells produce NO which binds with guanylate cyclase that produces guanosine triphosphate then transforms to guanosine monophosphate which is a potent vasodilator. It also prevents platelet aggregation and microthrombi.

Prostacyclin + Thromboxane A2 pathway. Prostacyclin is produced by the endothelial cells of arterioles. Prostacyclin binds with surface receptors of the smooth muscle cells, then activates ATP (adenosine triphosphate), and finally becomes cyclic AMP (adenosine monophosphate). AMP is anti-inflammatory and prevents platelet microthrombi.

Endothelin pathway.  Endothelin is a peptide, produced by the cell membrane of endothelial cells. It is a potent vasoconstrictor. Also produce smooth muscle hypertrophy, cell migration and fibrosis.

The reversible Hypoxic pathway.  The sympathetic nerve fibers abundantly supply even the smallest branches of pulmonary arterioles. The system is activated by chemoreceptors located in the carotid and aortic bodies. These receptors monitor PaO2 (partial pressure of oxygen); hypoxia causes reflex vasoconstriction and in prolonged hypoxemia migration of cells in and around arterioles produces fibrosis.

Clinical Classification of PAH:

PAH is categorized into 1. idiopathic, 2. familial, 3. secondary to other diseases, of which the most often are scleroderma and other collagen vascular diseases, HIV infection, portal hypertension, and congestive heart failure. 4. Drug induced and toxins.

Familial cases are due to the mutation of genes, the important gene mutations are: BMPR II, AIK I, ENG, SMAD 9, CAV 1, KCNK 3.

Drugs responsible for PAH are - Aminorex, Fenfluramine, Dexfenfluramine, Rapeseed oil, Benfluorex, several Serotonin reuptake inhibitors (SSRIs). Toxins - Tobacco smoke, chemical solvents.

Therapeutics:

There are no cures for pulmonary hypertension. Medications used for the treatment of systemic BP are ineffective in pulmonary hypertension. Treatment of pulmonary hypertension produces only slowing down the progression of the disease.

The following groups of drugs are used in pulmonary hypertension-

Phosphodiesterase inhibitors. - Sildenafil and Tadalafil.  Adenosine monophosphate and Guanosine monophosphates are converted to cyclic forms (c-AMP & c-GMP) by the action of adenylyl-cyclase and guanylyl-cyclase respectively. Cyclic AMP and cyclic GMP have a multitude of cellular functions including cell proliferation and growth. c-AMP and c-GMP are broken down by Phosphodiesterase. Sildenafil and Tadalafil inhibit the action of diesterase.

Soluble Guanylate cyclase stimulators. - Riociguat.  It increases intracellular cGMP.

Prostacyclin analogs. - Epoprostenol, Treprostinil, Iloprost. Prostacyclin produces smooth muscle relaxation, lowers pulmonary blood pressure, acts as an anti-inflammatory, inhibits platelet microthrombi.

Prostacyclin receptor agonist. - Selexipag. It is a vasodilator and prevents platelet adhesion.

Endothelial receptor antagonist. - Bosentan, Ambrisentan, Macitentan. Endothelin is a vasoconstrictor and increases pulmonary BP. These drugs prevent binding of Endothelin to its receptors and blunt the endothelin actions.

Additional agents used in the treatment of pulmonary hypertension are Oxygen, diuretics, nutrition and pulmonary rehabilitation.

Pulmonary hypertension detection by doppler echocardiogram is very useful for the diagnosis of new cases and monitoring the effects of therapy. More research is needed in pulmonary hypertension and in finding effective and less toxic drugs.

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Pleural Effusion - Cause and Mechanism:

 

                                                              Pleural Effusion

                                                      Mechanism and Causes

                                                    PKGhatak, MD

A small amount of pleural fluid is produced by the parietal pleura (a thin layer covering the inside of the chest wall, diaphragm and hilum), just enough to lubricate both layers of pleura so that during breathing the two surfaces slide smoothly one over the other without friction. The fluid does not accumulate because just as the fluid is produced continuously, the fluid is drained continuously by the lymphatic channels of the parietal pleura. Pleural effusion develops when excess fluid is produced or removal is delayed.

Clinical Types of Pleural Effusion:

It is useful to classify pleural effusion as Transudate and Exudate.

Transudate fluid is thin, has a low protein concentration, low LDH, and has none to two WBCs.

Transudate pleural effusion takes place because the fluid oozes out of the lung alveoli due to high capillary pressure. The most common cause of it is congestive heart failure, Nephrotic syndrome, cirrhosis of the liver, hypoalbuminemia from malabsorption syndrome, protein losing enteropathy and acute left ventricular failure, Pulmonary edema, and massive pulmonary embolism.

Mechanism of Transudate. Like liver nodules, the alveoli of the lung have a dual blood supply. The pulmonary artery brings in venous blood to the alveolar capillary. This is the source of most blood in the lung. In overloaded heart chambers in congestive heart failure, the pressure rises in heart chambers sharply. The back pressure is felt in the capillaries of the alveoli. When the pressure exceeds the oncotic pressure of blood, the water and dissolved solutes leak out in the interalveolar and pleural spaces resulting in pleural transudative pleural effusion.

Mechanism of Exudate: Inflammation of pleura by bacteria, mycobacteria tuberculosis, and fungus is generally due to the extension of lung infection. The pleural fluid is characterized by the presence of over 50% serum albumin concentration and over 60% LDH of the serum. The sugar concentration of the fluid in pneumococcal pleural effusion is low and has a high WBC count. 

Clinical subtypes of pleural effusion.

Empyema. In certain infections, the WBC numbers are so numerous that the pleural fluid becomes white cloudy- called empyema. Common causes of empyema are lung abscess rupturing in the pleural space, infected stab wounds, septicemia, post operative chest wounds. contaminated traumatic chest wall injuries.

Hemorrhagic Pleural Effusion. Traumatic chest wall injuries, contusion, laceration and infarction of the lung produce hemorrhage in the pleural space. Coagulation abnormalities either secondary to medical therapy, thrombocytopenia (platelet count 50,000 or less), deficiencies of coagulation factors or circulating anticoagulants may produce hemorrhagic pleural effusion.

Malignant Pleural Effusion. Malignant tumors of pleura are rather rare, only mesothelioma was an exception. In general, malignant pleural effusion is secondary to known lung malignancy, common in metastatic breast, ovary, colon cancers and primary lung cancer, lymphoma, and leukemias.

Chylous Pleural Effusion. The pleural fluid appears milky due to the presence of chylomicron. Chylomicrons contain long chain fatty acids, cholesterol esters, phospholipids. This condition results from obstruction or laceration of the thoracic duct. Cancer of the apical section of the lung. Pancoast tumors, lymphoma, and tuberculosis and filariasis cause obstruction of the thoracic duct. Fractures of 1st rib, sternum and upper thoracic vertebrae may cause laceration of the thoracic duct.

Bilateral Pleural Effusion. It is due to systemic diseases like CHF, nephrotic syndrome, cirrhosis, etc.

Unilateral Pleural Effusion. Unilateral effusion is due to one sided pleural disease but subsequently may be bilateral, if the disease spread to the other side. Example- pneumonia.

Localized Pleural effusion. The accumulated pleural fluid is walled off by fibrin and coagulated proteins.

Pleural Thickening. In tubercular pleural effusion, if the pleural fluid is not by evacuated by thoracentesis or drug therapy, layers of fibrous tissues are deposited over the surface of the lung like a straitjacket and prevent the expansion of the lung during breathing.

Cryptogenic or Unknown Causes of Pleural effusion. The effusion may start as unilateral or bilateral, and transudate effusion may turn exudate. In long term follow up and repeated pleural biopsies, detect about 10% due to mesothelioma or carcinoma of the lung. The cause of the remaining cases remains unknown.

Chronic Pleural Effusion. This condition is usually associated with end organ failure.

Rare causes of Pleural Effusion.

Meig's syndrome. Pleural effusion and ascites are associated with a benign ovarian tumor.

Ovarian Overstimulation Syndrome. Injectable fertility drugs to generate eggs in ovaries may produce capillary leaks and ascites and pleural effusion may develop.

Post Radiation Therapy also for the same reason produces this complication.

 Allergic drug reactions, Collagen vascular diseases and Autoimmune diseases can cause a mild form of vasculitis and pleural effusion.

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Multiple Myeloma

                                                          Multiple Myeloma

                                                   PKGhatak, MD

Multiple Myeloma (MM) is a cancerous disease of the Plasma cells of the bone marrow. It is a disease of the elderly and the condition is not inherited nor are there any known risk factors; but hepatitis C, HIV infection and Chronic Lymphocytic leukemia (CLL) patients have a higher incidence of MM.

MM is the final stage of a spectrum of plasma cell dyscrasias which starts as monoclonal gammopathy of unknown significance (MGUS) to overt plasma cell leukemia to extramedullary myeloma and finally to MM with end organ damages.

Epidemiology:

MM is very rare in people under 35 years. old. The annual incidence of MM in the USA is 300,000/yr. and 12,000 people die from MM. The worldwide incidence of MM is 80,000/yr.  New Zealand and Australia have more MM per 100,000 population. In the USA, the rate is 8.2 in white men, 5.0 in women, 16.5 in black men and 12.0 in black women per 100,000 population. For Hispanic men and women, the rates are 8.2 and 5.7 respectively and the rate for Asian/Pacific islanders at 5.0 in men and 3.2 in women.

Plasma Cell.

                                            Plasma cell..

About 2 to 3% of cells in the normal bone marrow are plasma cells. Plasma cells are large and have an eccentric nucleus, coarse chromatin and large cytoplasm.

In health, the majority of plasma cells are found in the active bone marrow and a few are also found in the spleen, lymph nodes and other tissues. In adults, the most active marrow is located in the vertebrae, scapula, sternum, skull bones, ribs and pelvis. The plasma cells are derived from B-lymphocytes (B-cells). B-cells are activated by a specific foreign antigen, which is introduced to them by the Dendritic cells. Activated B-cells in lymph nodes survive only 4-5 days. Some activated B-cells move to the bone marrow and live for a very long time. Bone marrow plasma cell keeps that antigen memory permanently. When challenged again with the same antigen, they quickly produce IgM antibodies (Immunoglobulin) and 10 days later start making IgG antibodies and keep producing antibodies as long as that antigen remains in the body or is reintroduced at a later time. IgA, IgD, IgE antibodies are also produced by plasma cells in various amounts and based on their location in the tissue/organ.

Effects of Uncontrolled growth of Plasma cells.

Rapidly multiplying plasma cells displace other blood forming cells, and soon the plasma cells number grows to 60 to 80 % of the bone marrow blood forming cells. RBC, WBC and Platelet numbers decrease and anemia, recurrent infection and easy bruising develop. The secretory product of plasma cells is immunoglobulins. In MM the immunoglobulins are abnormal in both structure and amounts. The accumulated immunoglobulin in blood makes blood more viscous and blood circulation in capillaries becomes sluggish, particularly in the retinal vessels, producing retinal hemorrhage and decreased visual acuity. The lambda and kappa light chains of immunoglobulins are excreted in urine, and gradually renal function deteriorates. Bone spicules dissolve and lytic lesions are detected in an x-ray. Blood calcium levels rise in proportion to bone lysis and osteoporosis and high serum calcium usually leads to a serious medical emergency.

Symptoms of MM:

In those days before Google search, medical schools came up with mnemonics to help students memorize certain important symptoms of a disease. CRAB stood for symptoms of MM. C=calcium increase in blood, R= renal function deterioration, A= anemia, B=bone pain. Bone pain is worse at dawn and dusk and increases in intensity with physical activities. Another mnemonic is Poem syndrome. P=peripheral neuropathy, O=organomegaly,  E= endocrinopathy. M=macroglobulin levels. S=skin pigmentation changes.

 Various peripheral nerves are involved, the Liver, and the spleen are enlarged, and many endocrine secretions are suboptimal. Thicken skin, changes in hair growth over the face, chest, limbs, and edema of legs and feet may develop. Other symptoms are weight loss, weakness, fatigue, confusion, and dementia.

Clinical subtypes of MM:

1. Indolent MM - patients are asymptomatic, plasma cells are up 10% or more of the blood cells in the bone marrow. M protein in blood is 3gm/dl. or more.

2. Solitary Plasmacytoma of the bone - a single tumor is present and no symptoms.

3. Extramedullary Plasmacytoma - plasma cell tumors develop in the upper airways, nose, nasal sinuses, larynx, GI tract, breasts and brain.

4. Bence Jones proteinuria or presence of light chains in urine.

5. Nonsecreting Myeloma.

6. Waldenstrom macroglobulinemia. Both B-cells and Plasma cells produce excess Macroglobulin. Various symptoms develop due to high blood viscosity from the excess macroglobulin.

7. Rare IgD and IgE myeloma. IgD myeloma is seen at relatively younger age. IgE myeloma is an aggressive type.

Diagnosis of MM:

A bone marrow biopsy is essential. MM diagnosis is made when the Plasma cell population is over 10%, usually at the time of diagnosis plasma cells are over 50%. Other positive findings are high microglobulin in blood and urine. Bone x-ray show lytic lesions and pancytopenia but these additional findings are not required for the diagnosis of MM.

Staging:

The international staging system categorizes MM into 3 stages based on blood tests:

Stage I. - Serum beta-2 microglobulin over 3.5 mg/L and serum albumin at/ over 3.5 g/dL. 

Stage II. serum levels are between the values of stage I and stage III.

Stage III. - Serum beta-2 microglobulin at or over 5.5 mg/L and high LDH (lactic dehydrogenase).

Revised International staging system (R-ISS):

Stage I. B-2 microglobin  < 3.5mg/L, albumin > 3.5d/L, no cytogenic abnormalities in iFISH (interphase fluorescence in situ hybridization).

Stage III. B-2 microglobin  >3.5 mg/L, High LDH, Presence of iFISH abnormalities. In MM the iFish cytogenic abnormalities are - deletion of 17p and/or t 4;14, and/or t 14;16. (p= short arm of chromosome 17. t=translocation of oncogene at 14;4 location).

Treatment of MM:

The current trend in the treatment of hematological malignancy is to perform Stem Cell Transplantation early. In MM the preferred age for stem cell transplant is below 75 yrs. Two different stem cell transplants are possible in MM. These are Autologous (patient's own stem cells) and Allogenic (HLA matched stem cells from the donors).

Targeted Therapy.

  - Proteasome inhibitor therapy. Proteasome is a protein that clears unused protein molecules from a dividing cell. If that clearing protein is blocked, then the dividing cells are choked with proteins and die. That is the basis of proteasome treatment. Drugs available are Bortezomib, Carfilzomib and Ixazomab.

- Monoclonal antibody therapy (mAb). The commonly use mAbs are Daratumumab for bone pain, Elotuzumab for accelerated killing by phagocytes.

- Histone Deacetylase (HDAC) inhibitors. These drugs block cell division. The available drug is Panobinostat.

- BCL-2 Inhibitor. Helps to kill cancer cells. Drugs available are Veneloclax.

Immunotherapy. Thalidomide accelerates the killing of rapidly dividing malignant cells. Derivatives of thalidomide are more powerful than thalidomide. Available drugs are Lenalidomide and Pomalidomide.

CART Therapy.  Surveillance T-cells have surface receptors by which T-cells attach to the foreign antigen. Because cancer cell antigen closely resembles the normal cell of the body, at times the receptors fail to bind with the cancer antigen. Mutated cancer cells have acquired this strategy and evade detection and death. In the CART therapy laboratory engineered Chimeric Antigen Receptors and T-cells from the patient are incubated together. These special T-cells are made to multiply in the laboratory and later transfused to patients to enhance tumor killing.

Chemotherapy. - A combination of 4 to 6 chemotherapeutic agents is administered in 4 to 6 cycles over 6 months to induce remission. Cyclophosphamide, Doxorubicin and Etoposide are commonly used in MM.

Treatment strategy for MM. - The first step is to induce remission through a combination of immunotherapy, targeted therapy and chemotherapy. The number of agents used in the combination varies according to the disease stage of patients. Then Watchful Waiting. Maintaining remission is usually achieved by immunotherapeutic agents.

If a recurrence of MM is detected, a Stem cell transplant is advised provided there is no contradiction.

Then again, a watchful waiting with maintenance therapy, and surveillance.

Prognosis:

The prognosis: Survival used to be 5 years for stage I, and for stage II and stage III rates were 3.5 yrs. and 2.5 yrs. respectively. In a 2021 publication, the 5-year survival rate was noted to be 75% in early cases, and in late diagnosed cases the rate was 48%.

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