RESPIRATORY DISEASE
Ed Friedlander, M.D., Pathologist
scalpel_blade@yahoo.com

Cyberfriends: The help you're looking for is probably here.

Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.

DoctorGeorge.com is a larger, full-time service. There is also a fee site at www.afraidtoask.com.


If you have a Second Life account, please visit my teammates and me at the Medical Examiner's office.

Freely have you received, give freely With one of four large boxes of "Pathguy" replies.

I'm still doing my best to answer everybody. Sometimes I get backlogged, sometimes my E-mail crashes, and sometimes my literature search software crashes. If you've not heard from me in a week, post me again. I send my most challenging questions to the medical student pathology interest group, minus the name, but with your E-mail where you can receive a reply.

Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource. Someday you may be able to access these pictures directly from this page.

I am presently adding clickable links to images in these notes. Let me know about good online sources in addition to these:

Freely have you received, freely give. -- Matthew 10:8. My site receives an enormous amount of traffic, and I'm handling about 200 requests for information weekly, all as a public service.

Pathology's modern founder, Rudolf Virchow M.D., left a legacy of realism and social conscience for the discipline. I am a mainstream Christian, a man of science, and a proponent of common sense and common kindness. I am an outspoken enemy of all the make-believe and bunk that interfere with peoples' health, reasonable freedom, and happiness. I talk and write straight, and without apology.

Throughout these notes, I am speaking only for myself, and not for any employer, organization, or associate.

Special thanks to my friend and colleague, Charles Wheeler M.D., pathologist and former Kansas City mayor. Thanks also to the real Patch Adams M.D., who wrote me encouragement when we were both beginning our unusual medical careers.

If you're a private individual who's enjoyed this site, and want to say, "Thank you, Ed!", then what I'd like best is a contribution to the Episcopalian home for abandoned, neglected, and abused kids in Nevada:

I've spent time there and they are good. Write "Thanks Ed" on your check.

Help me help others

My home page
More of my notes
My medical students

Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles that you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review linked below. If you are interested in complementary medicine, then I would urge you to visit my new Alternative Medicine page. If you are looking for something on complementary medicine, please go first to the American Association of Naturopathic Physicians. And for your enjoyment... here are some of my old pathology exams for medical school undergraduates.

I cannot examine every claim that my correspondents share with me. Sometimes the independent thinkers prove to be correct, and paradigms shift as a result. You also know that extraordinary claims require extraordinary evidence. When a discovery proves to square with the observable world, scientists make reputations by confirming it, and corporations are soon making profits from it. When a decades-old claim by a "persecuted genius" finds no acceptance from mainstream science, it probably failed some basic experimental tests designed to eliminate self-deception. If you ask me about something like this, I will simply invite you to do some tests yourself, perhaps as a high-school science project. Who knows? Perhaps it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship by suspending their own reasoning and simply accepting a single authority that seems wise and good. I've learned that they leave the movements when, and only when, they discover they have been maliciously deceived. In the meantime, nothing that I can say or do will convince such people that I am a decent human being. I no longer answer my crank mail.

This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.

This page was last updated February 9, 2008.

During the thirteen years my site has been online, it's proved to be one of the most popular of all internet sites for undergraduate physician and allied-health education. It is so well-known that I'm not worried about borrowers. I never refuse requests from colleagues for permission to adapt or duplicate it for their own courses... and many do. So, fellow-teachers, help yourselves. Don't sell it for a profit, don't use it for a bad purpose, and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about your successes. And special thanks to everyone who's helped and encouraged me, and especially the people at KCUMB for making it possible, and my teaching assistants over the years.

Whatever you're looking for on the web, I hope you find it, here or elsewhere. Health and friendship!

We comply with the HONcode standard for trustworthy health
information:
verify here.

PicoSearch
  Help

More of Ed's Notes: Ed's Medical Terminology Page

Perspectives on Disease
Cell Injury and Death
Accumulations and Deposits
Inflammation
Fluids
Genes
What is Cancer?
Cancer: Causes and Effects
Immune Injury
Autoimmunity
Other Immune
HIV infections
The Anti-Immunization Activists
Infancy and Childhood
Aging
Infections
Nutrition
Environmental Lung Disease
Violence, Accidents, Poisoning
Heart
Vessels
Respiratory
Red Cells
White Cells
Coagulation
Oral Cavity
GI Tract
Liver
Pancreas (including Diabetes)
Kidney
Bladder
Men
Women
Breast
Pituitary
Thyroid
Adrenal and Thymus
Bones
Joints
Muscles
Skin
Nervous System
Eye
Ear
Autopsy
Lab Profiling
Blood Component Therapy
Serum Proteins
Renal Function Tests
Adrenal Testing
Arthritis Labs
Glucose Testing
Liver Testing
Porphyria
Urinalysis
Spinal Fluid
Lab Problem
Quackery
Alternative Medicine (current)
Alternative Medicine (1983)
Preventing "F"'s: For Teachers!
Medical Dictionary

Courtesy of CancerWEB

Herbert Spencer Image Library
Wonderful collection from
the great lung pathologist

Upper Respiratory Images
University of Washington
Pictures and comments

Lung pathology
Aliya Husain MD -- Thanks!
Loyola U.

Pulmonary
Utah cases for path students
Juliana Szakacs MD

Lung pathology
Text and links to photos
Case Western Reserve

Respiratory
Iowa Virtual Microscopy
Have fun

Lung Pathology
Photomicrograph collection
In Portuguese

Pathology of respiratory infections
Great site
Yutaka Tsutsumi MD

Respiratory Diseases
First Section
Chaing Mi, Thailand

Respiratory Diseases
Second Section
Chaing Mi, Thailand

Lung Exhibit
Virtual Pathology Museum
University of Connecticut
Includes some gunshot wounds

Lung Transplant Pictures
Great site
Transplant Pathology Internet Services

Tulane Pathology Course
Great for this unit
Exact links are always changing

Lung and Respiratory System Review
Tulane
Dr. Daroca

Lung Pathology
Fantastic images
Martha Warnock -- UCSF

Respiratory I
Great pathology images
Indiana Med School

Respiratory II
Great pathology images
Indiana Med School

Pulmonary Pathology
Sampurna Roy, MD
Lots of photos and good text

Respiratory Pathology
Virginia Commonwealth U.
Great pictures

Gross Lungs
Tulane
Big selection

Pulmonary
Photos, explanations, and quiz
Indiana U.

Ordinary anthracosis of the lung
Brazil Pathology Cases
In Portuguese

Lung Pathology
Loyola
Nice pictures and comments

QUIZBANK: Respiratory

OVERVIEW OF RESPIRATORY DISEASE

Learn First!

Chest wall problems

Obstructed upper airway

Obstructed large bronchi

Constricted small bronchi

Fibrotic respiratory bronchioles... SILICOSIS

Collapsed respiratory bronchioles... EMPHYSEMA/"CHRONIC BRONCHITIS"

Fluid-filled alveolar spaces

Fluid-filled alveolar septa

Fibrosis around ulcerated bronchi...BRONCHIECTASIS

Fibrosis of alveolar septa

Collapsed alveoli

Necrotic lung ("cavities", etc.)

Pulmonary Hypertension

High PaCO2... all whole-lung ventilation problems

Low PO2...

STUDY OBJECTIVES

Describe the essential gross and microscopic anatomy of the airways, from trachea to alveolar sacs. Distinguish the two principal types of pneumocytes (I and II). Describe the anatomic and functional barrier to gas exchange at the alveolar-capillary level.

Describe the factors that influence PaCO2 and PaO2. Describe how PaO2 correlates with the actual oxygen content of the blood. Give the conditions when cyanosis will appear.

List the principal causes of edema in the lung, and compare these to things that cause edema anywhere else in the body. Distinguish interstitial and alveolar edema. Explain why edema of the lung is bad for one's health.

Describe pulmonary congestion, and mention its pathologic sequelae.

Review the pathology and pathophysiology of pulmonary thromboemboli. Describe their frequency and clinical correlations.

List the common causes of increased resistance in the pulmonary arteries (the usual cause of "pulmonary hypertension"), and other causes of pulmonary hypertension. Explain why these things are so harmful. Explain hypoxic pulmonary vasoconstriction, why it is useful in health, and why it is such a problem in disease.

Define acute / adult respiratory distress syndrome and list a few of the many synonyms. Tell about the etiologies, gross and microscopic pathology, the pathophysiology, and the common clinical picture.

Explain the pathophysiology and clinical correlations of neonatal respiratory distress syndrome.

Define atelectasis. Tell how lung collapses due to obstruction, compression, and lack of surfactant, and give clinical examples of each situation.

Define "sudden infant death syndrome". Briefly describe what we think causes genuine "SIDS", and give a "differential diagnosis".

Ed on Blood Gases * Review how to order "arterial blood gases", what you get, and what they tell you. (Be able to do this at 3 AM as the only doctor on the ward.) This might be a good time to look at the Blood Gases" handout.

Describe the abnormal anatomy and functional problems that every cigaret smoker should expect.

Explain the importance of elastic recoil in keeping respiratory bronchioles patent during exhalation. Explain how this relates to the classic definition of emphysema as "an abnormal, permanent dilatation of part of all of the acinus, with destruction of alveolar walls."

Distinguish the two "classic" types of emphysema, and mention their alleged causes. Tell what we think causes emphysema in cigaret smokers and alpha-1 antitrypsin deficient patients. Tell what a "pink puffer" looks like clinically, and how emphysematous lungs look at autopsy. Describe the complication of "bullous emphysema".

Define "chronic bronchitis" and mention its common causes. Describe the gross and microscopic pathology and the pathophysiology. Be able to define the "Reid Index". Tell what a "blue bloater" looks like clinically, and mention the common organisms that superinfect these patients' lungs.

Define bronchial asthma. Describe its important causes, and distinguish "allergic" and "idiosyncratic" kinds. Describe the common pathophysiology. Tell what you will see at the autopsy of an asthmatic. Mention other causes of wheezing.

Define bronchiectasis. Describe the important causes, the abnormal anatomy, and the typical clinical picture.

Describe the various breathing problems that occur during sleep. Recognize sleep apnea as a common cause of several illnesses.

Describe the normal flora of the lungs in non-smokers and smokers, and recognize the range of micro-organisms that have caused lung infections. Recognize the tremendous clinical importance of lung infections.

Distinguish bronchopneumonia, lobar pneumonia, and pneumonitis. Describe the typical histopathology of lung infections caused by various agents.

List the etiologic agents of lobar pneumonia, the classic stages in its progression, the major complications, and those at risk for each form.

Describe the causes, underlying problems, pathophysiology, and morbid anatomy of bronchopneumonia, aspiration pneumonia, legionellosis, pneumocystosis, lung abscess, and viral and mycoplasmal pneumonias. Describe the distinctive features of hantavirus infection and SARS (the 2003 epidemic).

Describe the anatomic pathology, pathophysiology, and clinical picture of the "idiopathic pulmonary fibrosis" family of diseases. Identify "Hamman-Rich" syndrome, and mention its likely cause.

Define sarcoidosis, and describe a typical sarcoidosis patient. Explain the usual effects of sarcoidosis on the lungs, skin, and eyes. Mention the serious consequences of untreated sarcoidosis. Describe the histology, and give a differential diagnosis for a granuloma found on biopsy. Explain how sarcoidosis causes abnormalities of calcium metabolism. Recognize the Kveim test as of limited usefulness. Tell how to make the diagnosis of sarcoidosis, and how to treat sarcoid patients.

Explain the essential lesion of Goodpasture's disease involving the lung, and mention the clinical picture and diagnostic lab test, and essential treatment. Mention some "related" (?) causes of bleeding from the pulmonary alveoli.

Briefly describe the eosinophilic pneumonias, and the various lipid pneumonias and lipoproteinosis, focusing on their histopathology.

Give the numbers of new cases of lung cancer in U.S. men and women expected this year. Explain how rates are changing, and why. Describe the risk factors for lung cancer, mentioning the importance of cigaret smoking, industrial exposure, radon in the home, and indoor air pollution.

Barney Rubble Explain how and why pathologists subclassify lung cancers. Recognize each of the nine members of the WHO-1999 classification:

Describe the important distinctions among the various types. Identify the common lung cancers under the microscope. Explain how pathologists use each of these to distinguish primary lung tumors:

Tell how bronchogenic carcinomas present. Describe the various paraneoplastic syndromes seen with lung cancer, especially the hypercalcemia syndromes and the small cell undifferentiated carcinoma syndromes.

Identify bronchial carcinoid, tell how it looks grossly and microscopically, how to recognize it, and describe its origin and its variants.

List the common problems that affect the larynx or trachea. List the different kinds of pleural effusions, and tell the significance of each. Describe the various kinds of pneumothorax and why they are important. Tell how pleural plaques look and what causes them.

Identify the cell of origin, risk factor, gross and microscopic appearance, and prognosis for malignant mesothelioma.

Mention the basic biology of ciliary dyskinesia syndromes, tell when you would suspect one, and how you would verify it.

As usual, given a gross lung or larynx, or a biopsy of any level of the respiratory tract, recognize any of the lesions exhibited in this section with at least 70% accuracy.

Healthy lungs
Freshly-opened at autopsy
WebPath

Healthy lung
Formalin-inflated
WebPath

Pulmonary surface lymphatics
A bit accentuated due to pulmonary edema
WebPath

Healthy lung
Photomicrograph
WebPath

Life is not measured by the number of breaths you take, but by the number of moments that take your breath away.
        -- Attributed to George Carlin

NORMAL ANATOMY AND PHYSIOLOGY

PULMONARY CONGESTION AND EDEMA

{37956} pulmonary edema gestalt

{10145} pulmonary edema (just enough protein content to stain...)
{11666} pulmonary edema

Pulmonary Edema
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery

Pulmonary edema
Some stainable protein, hence an exudate
WebPath

Heart Failure Cells
Slide from Andrea McCollum MD
Cuyahoga County Coroner's Office

Heart Failure Cells
Hemosiderin-laden macrophages in the lung
KU Collection

PULMONARY EMBOLIZATION ("embolism") AND INFARCTION (NEJM 358: 1209, 2008; Lancet 363: 1295, 2004)

{29052} pulmonary embolus, ancient, organized and turned into fibrous bands

Pulmonary Embolus
Photo and mini-review
Brown U.

Pulmonary Thromboembolus
Australian Pathology Museum
High-tech gross photos

Pulmonary thromboembolus
Autopsy photo
KU Collection

Pulmonary thromboembolus
WebPath

Saddle embolus
WebPath

Lung infarct
WebPath

Lung infarct
WebPath

Pulmonary embolus
Actually, ALL antemortem thrombi are layered
WebPath

Pulmonary embolus
WebPath

Pulmonary embolus
WebPath

Pulmonary embolus
WebPath

Old pulmonary embolus
Organized
WebPath

Pulmonary infarct
Urbana Pathology

Pulmonary embolus
Animation

Thanks, Webpath

PULMONARY HYPERTENSION

Pulmonary Arterial Sclerosis
From Chile
In Spanish

Vascular Lung Disease
Text and links to photos
Case Western Reserve

Talc in the lungs
Pulmonary hypertension in druggies
WebPath

Plexiform lesion
WebPath

Pulmonary hypertension
Narrowed artery
WebPath

Crystals in the lungs of drug abusers
Lung pathology series
Dr. Warnock's Collection

ACUTE / ADULT RESPIRATORY DISTRESS SYNDROME (ARDS -- update Lancet 369: 1553, 2007)

Gassed
WWI painting
Mustard gas victims
John Singer Sargent

    This very common problem, deadly, and expensive problem results from anything that severely injures the type I pneumocytes and capillary endothelial cells throughout the lungs.

      There are at least 150,000 ARDS cases in the U.S. every year (as an autopsy pathologist, I'd say this about right).

    Da Nang ARDS first came to be recognized during the Vietnam War.

      Soldiers who had survived extremely severe injuries and seemed to be recovering would suddenly develop intractable shortness of breath and die in a few days.

      It was called "Da Nang lung". Originally there was concern about biological warfare. But it soon became clear that the pulmonary changes were remote effects of injuries that previous soldiers did not survive.

    ARDS has many causes. These include...

    • sepsis (the most common single cause)

    • shock itself

    • oxygen toxicity

    • lung contusion

    • viral infections of alveolar epithelium (influenza, herpesviruses, Navajo hantavirus Lancet 347: 739, 1996, others)

    • burns

    • radiation

    • drugs (notably certain cancer chemotherapy agents, also remember amiodarone)

    • poison gas

    • silo-filler's disease (treacherous, since the inhaled nitrogen oxides hydrolyze into nitric / nitrous acid several hours after exposure; reviews Mayo Clin. Proc. 71: 813, 1996; Ann. Int. Med. 141: 410, 2004)

    • near-drowning

    • the heart-lung machine

    • aspiration of gastric contents

    • severe multi-organ injury

    • blood transfusion ("transfusion-associated acute lung injury"; antibodies against HLA and/or neutrophils in the donor plasma and/or lipids in banked blood that anger the patient's own neutrophils Am. J. Clin. Path. 121: 590, 2004. Quite common and usually mild, this can be deadly. Nowadays this is probably the most common cause of death from blood transfusion.

    • pneumocystosis

    • * gene therapy ("Jesse Gelsinger's disease" -- Science 288: 951, 2000, Sci. Am. 282(2): 36, Feb. 2000.)
    • Even high-pressure mechanical ventilation itself wrecks this havoc on the lungs (Am. Rev. Resp. Dis. 143: 1115, 1991).
    So ARDS also has many synonyms, including shock lung, traumatic wet lung, diffuse alveolar damage, "nonhydrostatic pulmonary edema", "high-permeability low-pressure pulmonary edema", white lung, etc. etc.

    Mechanisms of injury are complex, with free radicals, complement, enzymes from marginated polys (can't be the whole story, since the neutropenic can and do get ARDS), microthrombi, aggregation of polys, "shock toxins", and many other ideas.

      The major experimental model involves reperfusion of an animal's hindlimb rendered ischemic for a considerable time (J. Traum. 31: 760, 1991).

      Interleukin-8, a great neutrophil attractant, abounds in fluid from ARDS lungs. We don't know why, but this probably has a lot to do with the problem.

    Biopsy is often helpful to establish an underlying diagnosis even though these people are very sick (Chest 125: 197, 2004. Here are some tips for guessing the cause of ARDS

    • Oxygen toxicity: Collagen confined in the walls and/or as masses in the lumens

    • Paraquat: Alveoli still well-defined but packed with dense scar

    • Chemotherapy: type II pneumocytes are very prominent and have big, bizarre nuclei

    • Radiation, short interval: Fatty change of the myointimal cells of arteries

    • Radiation, longer interval: type II pneumocytes have hyperchromatic nuclei; small arteries are hyalinized

    • Heroin: Edema is predominant

    • Certain amphophilic drugs, notably clomipramine: Clusters of foamy macrophages / "alveolar proteinosis"

    • Hantavirus: Very abundant T-immunoblasts

Hantavirus Pneumonia
Immunoperoxidase
Dr. Hjelle

Hantavirus
Electron micrograph showing
damaged basement membrane

    Whatever causes the injury, the result pretty much the same:

      When the alveolar cells are injured fluid leaks into the interstitial spaces and alveolar air spaces -- this is pulmonary edema.

      Later, with cell necrosis, fibrin is released into the alveoli, producing hyaline membranes. Of course there is loss of surfactant, so many alveoli collapse.

        During this early stage, the patient is very tachypneic and dyspneic, but the chest x-ray looks normal. (Why?)

        NOTE: In "respiratory distress syndrome" or "hyaline membrane disease" of low-birth-weight infants, the lack of surfactant is one primary problem, though not the only one. In ARDS, surfactant is decreased secondary to diffuse alveolar damage.

          * Surfactant aerosol-replacement flops for ARDS: NEJM 334: 1448, 1996.

      As type I pneumocytes are destroyed, type II pneumocytes divide to replace them ("regenerative epithelial hyperplasia" or "cuboidalization" of alveolar epithelium.) Of course, they are not so permeable to oxygen as the healthy type I cells.

      Fibrosis ensues as the intra-alveolar hyaline membranes and the interstitial exudate organize (Am. J. Path. 126: 171, 1987).

        Of course, fibrotic lung (from any cause) is prone to develop bacterial infections (bronchopneumonia), since it is harder to mobilize the exudate and perhaps the neutrophils must travel farther in pursuit of the microbes.

      Even where the alveoli remain ventilated, these factors combine to cause poor pulmonary compliance plus poor response to oxygen therapy ("alveolar-capillary block" in damaged alveolar walls; I'm inclined to believe in this.) Further, the pulmonary vascular bed is progressively obliterated.

ARDS
WebPath

ARDS
Hyaline membrane
WebPath

ARDS
UHS Case
Photo by Ed

ARDS
Urbana Pathology

ARDS
Photomicrograph
KU Collection

{06359} ARDS

    The outcome depends on whether the patient can be supported and the underlying problem successfully treated before fibrosis becomes extensive.

      High-dose steroids were tried in the '80's and failed to affect the outcome: NEJM 317: 1565, 1987. Fluid ventilation (i.e., breathing fluorocarbons), surfactant therapy, and nitric oxide therapy are all "still unproven" as well.

      Nobody knows exactly why (maybe relieving the weight pressing on the pulmonary veins), but putting the patient prone often helps oxygenation in the short-term (thought not long-term survival: NEJM 345: 568, 2001).

      About 50% of patients with ARDS die from it. Long, agonizing periods on the ventilator are fairly common. The ARDS autopsy and clinical correlations: Ann. Int. Med. 141: 440, 2004.

      * Today, there is considerable interest in factors that enhance regeneration of the pulmonary endothelial cells (J. Clin. Inv. 116: 2316, 2006).

      * With more patients surviving ARDS nowadays, there is considerable interest in the quality of these survivals. There is often brain damage sufficient to impair the quality of life (AJRCCM 171: 340, 2005), post-traumatic stress disorder (Am. J. Psych. 161: 45, 2004), and of course impaired lung function (Chest 123: 845, 2003; NEJM 348: 683, 2003).

NEONATAL RESPIRATORY DISTRESS SYNDROME ("hyaline membrane disease", HMD, RDS, etc.)

    This is the common cause of respiratory distress in premature infants (usually 1500 gm or under), beginning a few hours after birth.

    In addition to prematurity, risk factors include maternal diabetes, caesarean sections, premature rupture of the membranes. Heroin addiction or glucocorticoid administration in the mother protects from RDS.

    The pathophysiology is lack of surfactant plus high permeability of the immature pulmonary epithelium. A few air spaces are hyperinflated, the rest of the lung is collapsed.

      The principal lesion is probably necrosis of the respiratory epithelial cells; why this happens to premature infants is unclear but probably has something to do with their being unable to tolerate even normal amounts of inspired oxygen.

      Surfactant is also deficient in these patients and this accounts for part of the problem. Surfactant -- dipalmitoyl lecithin -- is the stuff that keeps the alveoli uniform in size. Recall the "two balloons on joining pipes" model in physiology.

      In RDS, hyaline membranes line the open alveoli (mostly along the respiratory bronchioles). As in ARDS, they result from plasma proteins exuding through the alveolar walls. (* These kids usually have patent ductus arteriosus with marked left-to-right shunting, which greatly exacerbates this problem.)

      As in ARDS, the presence of hyaline membranes is both a marker for alveolar membrane injury, and a further barrier to gas exchange.

{11427} hyaline membrane disease, newborn
{20014} hyaline membrane disease, newborn
{20015} hyaline membrane disease, newborn

Hyaline membrane disease
WebPath Photo

Hyaline Membrane Disease
Text and pictures
From "Big Robbins"

    To test for maturity of an unborn child's lungs, check the lecithin-to-sphingomyelin (L/S) ratio in amniotic fluid obtained by amniocentesis -- should be 1.5 or more.

    Until recently, treatment was limited to ventilatory support and oxygen, plus * drugs to dilate the pulmonary arterioles.

      During the last decade, administering surfactant into the lungs, before the first breath, has become standard. This is not a panacea.

      A significant number of low-birth-weight kids do suffer brain damage from hyaline membrane disease hypoxemia: NEJM 325: 276, 1991.

      * The extracorporeal membrane oxygenator (ECMO) is a modified heart-lung machine for preemies. The economic-ethical nightmares still happen.

      Big doses of oxygen cause further alveolar damage, resulting in fibrosis, which is given the unfortunate name of bronchopulmonary dysplasia (it is neither incipient cancer, nor a birth defect). Today it is better to call it chronic lung disease of infants.

        * An attempt to prevent bronchopulmonary dysplasia by administering inhaled glucocorticoids was a flop: NEJM 340: 1036, 1999.

        Bronchopulmonary "dysplasia"
        WebPath Photo

        Some of these kids get better in a few months, but the outcome is usually bad for both lung and brain (Pediatrics 77: 345, 1986). Many of these babies spend months or years on ventilators before finally dying.

    * Other problems of preemies: patent ductus arteriosus, meconium aspiration, necrotizing enterocolitis, cerebral hemorrhages from the germinal zone of the subependymal plate, preemie retinopathy (oxygen, bright lights).

    * In genetic absence of surfactant, babies born at term are unable to inflate their lungs. The disease is fatal: NEJM 350: 1296, 2004.

Newborn aspiration
WebPath Photo

Newborn aspiration
WebPath Photo

ATELECTASIS

Atelectasis
From Chile
In Spanish

    Collapse (or incomplete expansion) of pulmonary acini from any cause.

      Obstructive atelectasis (Baby Robbins and others call it absorption atelectasis) results from non-ventilation of alveoli that are still perfused; the alveolar gas is carried away by the bloodstream.

        Seen distal to tumors, foreign bodies, mucus blobs, post-surgical discomfort preventing cough, enlarged hilar nodes (cancer, TB -- producing "the right middle lobe syndrome") etc. Before antibiotics, this was a setup for bronchiectasis.

        If an airway is obstructed, expect that over time the alveoli will fill with surfactant, which will mostly be engulved by macrophages. This is the "obstructive pneumonia" or "golden pneumonia", and often is the first x-ray sign of lung cancer.

      Compressive atelectasis results from something in the pleural cavity (blood, exudate, tumor, air.)

        If extensive and unilateral, obstructive and compressive atelectasis can be distinguished by the direction in which the mediastinum is shifted on x-ray (think about it).

      A deficiency of surfactant produces "patchy atelectasis" in both hyaline membrane disease ("fetal atelectasis" -- * a term also used for lungs of stillborns who never breathed) and ARDS (see below.)

Atelectasis
This was from a hemothorax
WebPath

{10228} atelectasis (left lung of a baby whose left bronchus failed to form)

      Round atelectasis ("folded lung", "shrinking pleuritis"): a vanishing coin lesion, resulting when normal lung parenchyma is crunched into a little ball beneath a shrinking pleural scar. Familiar to radiologists, sometimes operated for diagnosis.

    Regardless of cause, atelectatic lung appears redder than inflated lung at autopsy, because the blood vessels are compacted. (In life, these vessels might not have been so well perfused, thanks to the hypoxic vascular response.)

SUDDEN INFANT DEATH SYNDROME ("SIDS", "crib death", "cot death", "continues to be the leading cuase of death for infants aged between 1 month and 1 year in developed countries" Lancet 370: 1578, 2007; "the seventh leading cause of years of potential life lost before age 65, commensurate with AIDS" -- MMWR 37: 644, 1988, etc., etc.). The following will upset you.

    Sudden death in an apparently healthy baby, less than one year old, with no explanation even after autopsy. Sources in the 1970's and 1980's claimed that this affected 2-3 per 1000 live births, "the single most common cause of infant death" (Baby Robbins, etc., etc.) -- slightly more common than baby death due to birth defects.

    There is no question that genuine SIDS cases exist, i.e., some babies do die from disturbed pathophysiology without any environmental or anatomic explanation. A few causes are known (i.e., channelopathy) or suspected (actual problems with respiratory drive; these must be rare). But to understand "sudden infant death", we first need to sort out deaths that aren't "SIDS" at all. Thankfully, this is now happening.

    During the 1960's, mostly because of the militancy of a single pediatrician-activist, certain anti-common-sense ideas about the sudden deaths of infants were suddenly and uncritically accepted, both by the medical community and by the public. Looking back, this had a lot to do with the "feel good / no blame / flower power" mentality of the times. It was dogma that:

    • A baby supposedly could not possibly smother to death by being placed face-down on a mattress.
    • A parent falling asleep on top of a baby, or a large toy in the crib, supposedly could not possibly asphyxiate the baby.
    • Sudden death of a baby supposedly resulted in almost all cases from a mysterious failure of the respiratory drive. To prevent this from happening, babies spent their first years attached to elaborate machines to alert the parents should breathing stop.
    • And of course, SIDS cases are not the result of anyone's negligence or actual malice. That would be unthinkable.

    That this was wishful thinking should have been obvious, even at the time.

    The classical autopsy finding in SIDS is petechiae over the thymus, lungs, and heart, without other abnormalities... or with nasal hemorrhages too. And this is exactly what you'd expect to find in a baby who has been suffocated -- accidentally, intentionally, on the bedclothes, or against the mattress (JAMA 263: 2865, 1990; Arch. Dis. Child. 85: 116, 2001).

    And it was already well-known that "higher rates are encountered in many developing countries" (Baby Robbins), and especially among the underclass in industrial countries (Practitioner 232: 577, 1988; Arch. Dis. Child 65: 830, 1990; risk for First Americans correlates with underclass risk factors rather than genes J. Ped. 121: 242, 1992; also & JAMA 288: 2717, 2002). Some classic reported SIDS death rates:

      0.04%... Rich New York suburbanites

      0.4%... Poor New York slum dwellers (both from NEJM 315: 100 & 126, 1986)

      0.35%... North Plains Indian reservations (JAMA, above)

      2% (!!) Children of British criminal offenders (Arch. Dis. Child. 62: 146, 1987.

      near zero... Hong Kong -- attributed to zero privacy and many helpers for mothers, no junk in the cribs, "nobody lets her baby sleep prone", "no unwanted babies": Lancet 2: 1346, 1985; Br. Med. J. 298: 721, 1989.

    It is now obvious that many (if not most) deaths signed out as "SIDS" during the decades of ignorance were the results of negligence or abuse by family members. This was substantiated in the 1980's by careful death-scene investigators (filicide Arch. Dis. Child. 60: 505, 1985; NEJM, above; Lancet 1: 313, 1986; Lancet 1: 199, 1989; J. Ped. 117: 351, 1990.)

    There was never any basis for believing that overlying cannot kill a baby. (King Solomon's judgement; Yeats's Moll Magee; most cultures historically have simply accepted that overlying kills babies.) See also Am. J. Forensic Med. & Path. (8): 256, 1987; when we stop kidding ourselves, overlying turns out to be common: Am. J. Dis. Child. 146: 968, 1992.) Sharing a bed with a parent as a risk for SIDS: Br. Med. J. 319: 1457, 1999; Arch. Path. Lab. Med. 126 343, 2002; J. Ped. 147: 32, 2005; Arch. Dis. Child. 88: 1058, 2003; Lancet 363: 185, 2004; Arch. Dis. Child 91: 318, 2006; Lancet 314: 367, 2006 ("Although the reason for the rise in deaths when a parent sleeps with their infant on a sofa are stil unclear, we strongly recommend that parents avoid this sleeping arrangement."). Sofas are worse and so is sleeping with Mom when she is drunk or on drugs (go figure; Arch. Dis. Child. 88: 112, 2003).

    Drug use by Mom ("during pregnancy", and of course most likely continuing after) is a very powerful risk factor for SIDS, especially when the drug is heroin or methadone, and when other risk factors (poverty, smoking, and so forth) are controlled-for (J. Ped. 123: 120, 1993). A classic observation is a higher incidence (+ 60% or so) of "SIDS" on weekends (Aust. N.Z. J. Med. 18: 861, 1988; still true Arch. Dis. Child. 89: 670, 2004), when Mom and Dad/current boyfriend are more likely to be drunk or stoned. This is every bit as true today as before the "back to sleep" campaign (Arch. Dis. Child. 89: 670, 2004 -- no surprise). And children of schizophrenic mothers have around five times the risk of "SIDS" (Arch. Gen. Psych. 58: 674, 2001).

    The fact that "SIDS is more than ten times more frequent if a sibling has already died of SIDS" (Arch. Dis. Child. 64: 179, 1989) hardly proves that "bad genes" are responsible. (No adoption studies are available yet....) The fact that SIDS rates are more than double for very young parents (J. Ped. 116: 520, 1990) hardly proves that some mysterious intra-uterine factor is involved. Nor does the fact that SIDS rates are double if the parents smoke (Am. J. Pub. Health 80: 29, 1990) prove that the cause is subtle irritation of the airways.

    And the fact that twins used to die of "SIDS" at exactly the same time invites an obvious conclusion (Am. J. Forens. Med. Path. 10: 200, 1989; AJFMP 19: 195, 1998). The fact that this no longer happens (Arch. Ped. Adol. Med. 153: 736, 1999) just says to me that pathologists are now recognizing obvious infanticide.

    The traditional wisdom that "SIDS" typically follows a minor illness now seems to be unfounded (Lancet 300: 1237, 1990). The claims about immunization being a risk factor are clearly untrue; statistically, children actually seem protected (Br. Med. J. 322: 822, 2001; the role of coincidence Pediatrics 115: e643, 2005).

    And the familiar junk-science claim by breast-feeding militants that SIDS is due to bottle feeding simply isn't true: Br. Med. J. 310: 88, 1995. At best, the relationship is statistical, and it's weak. However, the SIDS organizations still tell people that breast-feeding protects children from SIDS, which must put a terrible burden of guilt on people whose babies died of the real thing.

    Possibly a few infants do die from failure of respiratory drive during sleep. "Near-miss" apnea and related respiratory rhythm disturbances are demonstrable in some siblings, though the findings are notoriously un-reproducible.

      * I was impressed only by Hum. Genet. 73: 39, 1986 -- a family with very little myelin in the respiratory centers of their medullas). Since this hasn't been replicated, I wonder about the neuropathologist's myelin stain. Finding hypoplasia of the arcuate (CO2 sensor) nucleus of the medulla in a subset of SIDS is interesting: J. Neuropath. 51: 394, 1992; I'd bet these brains are those that don't respond to having the mouth and nose up against the mattress. An Italian group claims to have found "frequent alterations, mainly cogenital, of the autonomic nervous system" (Am. J. Clin. Path. 124: 259, 2005; also J. Clin. Path. 58: 77, 2005). More credible is a big study from Harvard (JAMA 296: 2124, 2006) on the serotoninergic neurons in the medulla in SIDS. Stay tuned.

      Otherwise, "near-miss apnea seen in siblings" is peculiarly non-lethal: Science 264: 197, 1994. I suspect that, in most cases, "near-miss SIDS" is Cheyne-Stokes respirations (as a junior med student sharing a call room, I was told I do this while asleep) or transient obstructive sleep apnea.

    It is now obvious that some cases of SIDS result from laying babies prone (Pediatrics 93: 814, 1994; Pediatrics 105: 650 2000; JAMA 273: 783, 1995, lots more). Most plausibly, sleeping babies might simply fail to move when their faces lie flat against mattress, and smother in this way.... (gee whiz) ... or rebreathe carbon dioxide, which is pretty much the same thing (Am. J. Dis. Child. 147: 642, 1993; J. Ped. 122: 874, 1993). This is consistent with some studies that strongly suggest prolonged hypoxia has occurred prior to death in many SIDS cases (Pediatrics 87: 306, 1991, others).

    There has been about a 50% reduction in "SIDS" in countries where there's been a campaign to get parents not to place their babies prone. The impact is extremely obvious (Lancet 363: 185, 2004). In the U.S., where "SIDS activists" insisted for two decades that "SIDS is not your fault and a child cannot smother against the mattress", the campaign was delayed. Figure out yourself how many children died as a result. "Suffocated prone: the iatrogenic tragedy of SIDS": Am. J. Pub. Health 90: 527, 2000. Strangely, in the US, breast-feeding militants are still pressuring women to sleep with their infants.

      * "Swaddling clothes" (remember these from the Christmas story?) are an ancient custom designed to keep children lying on their backs, perhaps to prevent SIDS: J. Ped. 141: 398, 2002.

    There's some interesting work on facial morphology in these kids -- their upper and lower jaws seem to be, on average, farther back, and perhaps this makes it easier for them to smother on their mattresses (Lancet 317: 293, 1998). The relationship with obstructive sleep apnea -- which this group claims is more common in SIDS families -- is going to take more study to work out.

    SIDS
    Instructional material
    WebPath Photo

    When you are working in the neonatal intensive care unit, you will frequently see preemies that have trouble breathing or even stop breathing ("apnea of prematurity") or suffer cardiac rhythm disturbances. That thes have nothing to do with SIDS was estaboished long ago (Pediatrics 77: 811, 1986; Pediatrics 78: 787, 1986); today it's treated with caffeine and this seems safe (NEJM 357: 1893, 2007.

    Public awareness of "SIDS" resulted in a huge "apnea monitor" industry (racket, or "expensive cover-your-butt stuff", as almost everybody will tell you nowadays). Today, the people who really know about SIDS laugh at the idea that monitors save lives (see, for example, Chest 91: 898, 1987; Can. Med. Assoc. J. 140: 1072, 1989), but they did keep parents from staying up all night watching their babies breathe. "Consensus document" on home monitoring: Pediatrics 79: 292, 1987; noncompliance or worse: Am. J. Dis. Child. 142: 1037, 1988. By 1994, the idea that apnea is an important cause of SIDS is dismissed by almost the entire scientific community, though still believed by physicians (Science 264: 197, 1994); however it's still routinely prescribed (Arch. Dis. Child. 84: 270, 2001). To clinch the matter, Waneta E. Hoyte, the mother whose "tragic story" led to the paper (Ped. 50, 646, 1972) that spawned the apnea monitor business confessed in 1994 to having smothered her five children. ("Their screaming made her feel useless": Ped. 93: 944, 1994).

    Some "clever" parents learn to stop their kid from crying by smothering it into unconsciousness; this will load the lungs with hemosiderin-laden macrophages (why?). Eventually, these kids are likely to die. Pathologists are now routinely signing "SIDS" cases with lots of these macrophages as "manner of death undetermined" (J. Clin. Path. 52: 581, 1999) and staining all infant lungs to see hemosiderin (Am. J. For. Med. Path. 23: 360, 2002).

      The British put kids with near-miss SIDS on secret video in two hospitals, and videoed THIRTY of them being intentionally suffocated or strangled by a parent to quiet them (Pediatrics 100: 735, 1997). The conclusion was the understatement of the year: "When parents have failed to acknowledge that they have deceived health professionals, partnership with them in seeking to protect their children may be neither safe nor effective." Nowadays, even when the death certificate might originally have said "SIDS" or some other natural cause, many perpetrators are being successfully prosecuted: Arch. Dis. Child. 80: 7, 1999.

      * Believe it or not, some "ethicists" got very upset over the invasion of the British parents' privacy and "breach of trust" between the medical community and the abusers (Med. J. Aust. 160: 352, 1994).

      The British estimate that 1 in every 10 SIDS cases is a covert homicide (Arch. Dis. Child. 89: 443, 2004); whatever you think of the estimate, common-sense tells you when to suspect murder. SIDS "research" and political agendas: Arch. Dis. Child 88: 1085, 2003.

    Before you write "SIDS" on a death certificate, try to rule out:

    • upper respiratory infection (especially winter cases, when "SIDS" is most common)
    • long QT interval syndrome (channelopathy, I predicted this one; NEJM 338: 1709, 1998; Circ. 104: 1158, 2001; Lancet 358: 1342, 2001; JAMA 286: 2264, 2001 decided it's about 2% of SIDS cases; more sodium channelopathies in SIDS that weren't known previously Circulation 115: 368, 2007; estimate's up to about 10%: Circulation 115: 361, 2007)
      • Your instructor predicts that medical examiners will soon order "molecular autopsies" routinely in apparent SIDS, looking for channelopathies. Further, I predict the yield of positive results will be higher than 2%, and that this will even be recognized as a life-saver for relatives.

        It will be fairly expensive, but I think it's a responsible use of tax dollars. It prevents family members from "wondering if it was their fault" or "deciding it must have been the immunization."

    • streptococcus B infections (newborns)
    • epilepsy resulting in apnea
    • adrenal insufficiency (you couldn't have missed this at autopsy, however...; J. Ped. 145: 178, 2004)
    • botulism (ask about the baby having been fed raw honey)
    • obstructive sleep apnea (newly described -- there is at least one familial small-throat syndrome, see Lancet 1: 402, 1986; Arch. Dis. Child. 61: 1039, 1986), and probably more (Pediatrics 83: 647, 1989). Huge tonsils: For. Sci. Int. 53: 93, 1992. NOTE: Many monitor-detected "apparent life-threatening events" precede the development of classic sleep apnea when these kids get older (Chest 102: 1065, 1992, no surprise).
    • malformations of the brain stem and/or base of the skull (one example is achondroplasia: Am. J. Dis. Child. 142: 989, 1988)
    • inborn errors of fatty-acid breakdown -- these children will have fatty liver and are likely to be misdiagnosed as Reye's syndrome at autopsy (Lancet 2: 1073, 1986; Pediatrics 78: 1052, 1986; Br. Med. J. 296: 11, 1987; this is rare, and you don't find the defect in ordinary SIDS J. Ped. 122: 715, 1993; Arch. Dis. Child. 66: 1315, 1991).
    • absence or anomalous origin of one or more coronary arteries (Pete Maravich made it to his 40's with no left main coronary artery, but many don't)
    • other cardiac malformation (J. Ped. 141: 336, 2002) -- in these cases, the child is usually awake when he/she falls over dead
    • "ectodermal dysplasia" with no sweat glands (surprisingly, this is easy to miss in life)
    • * vertebral artery occluded at the junction of the occiput and C1 by turning the head: Pediatrics 103: 460, 1999 (still hypothetical...)
    • carbon monoxide poisoning (how's that home heater working?)
    • early pertussis infection (whooping cough is rampant in Europe thanks to the anti-immunization movement; link with SIDS Pediatrics 114: e9, 2004)

    • unnatural death (including overlying by parent, suffocation by toys, bedclothes, or the waterbed (NEJM 319: 1415, 1988) or beanbag chair (NEJM 324: 1858, 1991), hyperthermia, shaken-baby syndrome without subdural bleeds -- contrary to popular (and groundless) "no-guilt" claims, all of these can and do kill babies -- and of course, murder by smothering, i.e., Mary Beth Tinning / Waneta Hoyte syndrome; see Pediatrics 91: 423, 1993.)

      * Kids with febrile seizures are not at increased risk for SIDS, so it is probably unacceptable to invoke a seizure as causal: Arch. Dis. Child. 86: 125, 2002.

    But after you've done all this, can your autopsy rule out smothering or all other forms of lethal trauma? In a word, "No" (Am. J. Dis. Child. 144: 137, 1990). The SIDS autopsy: J. Clin. Path. 45(S-11): 11, 1992.

      * The pathology lab has nothing to offer for the differential diagnosis of "near-miss SIDS" (Am. J. Dis. Child. 140: 484, 1986). Protocol for the SIDS autopsy: J. Clin. Path. 40: 481, 1987.

      When a second SIDS death takes place in a home, the pathologist's task is especially difficult. One big study concluded that most of these are natural, and that many are homicides, and that sorting them out definitively is impossible (Lancet 365: 29, 2005). Probably you have to call the child protection folks (Arch. Dis. Child. 88: 699, 2003).

      * SIDS in Israel (no scene investigations, almost no autopsies; cultures, bone scans, and rarely labs for metabolic disease): Arch. Dis. Child. 92: 697, 2007.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD, chronic air flow obstruction, * COAD, * CAWO, * chronic airway obstruction): The most common cause of activity-restricting disability in the U.S. Morphology and pathophysiology review explaining the obstruction: Lancet 364: 709, 2004. Clinical review (no surprises): Lancet 362: 1053, 2003.

Obstructive Lung Disease
Text and links to photos
Case Western Reserve

    "Chronic obstructive pulmonary disease" is a traditional and irrational grouping of four illnesses:

      1. chronic bronchitis
      2. emphysema
      3. asthma
      4. bronchiectasis.

      The term generates tremendous confusion, and I urge you not to use it.

    "COPD" includes two very common "diseases" that typically occur together.

      Chronic bronchitis causes obstruction to air flow because of edema, necrosis, fibrosis, and recurring infections in the bronchial tree.

        The walls do get thicker and this narrows the bronchial lumens. This has been confirmed by some good pathology studies (Am. Rev. Resp. Dis. 143: 1152, 1991; Chest 97(S2): 6S, 1990), and now we see it on high-resolution imaging studies (it's the littlest airways, of course: AJRCCM 173: 1309, 2006). Since this is not a feature of the lungs of asymptomatic smokers (Radiology 235: 1055, 2005), it seems reasonable to think that this is the real lession of a real disease.

        Although narrowing of the bronchial lumens ("thickening of the bronchial walls") interferes some with breathing, it's usually the severity of the co-existing emphysema that really disables these people.

        The vicious cycle of bacterial colonization, infection, and damage probably plays a part in the progression of the disease (AJRCCM 173: 991, 2006).

        Increased mucous secretions and hyperplasia of mucous-secreting glands by themselves, though typical of chronic bronchitis, are now thought not to contribute significantly to obstruction (i.e., it's not prolonged suffocating on hockers). Am. Rev. Resp. Dis. 128: 491, 1983; Am. Rev. Resp. Dis. 133: 942, 1986.

        * Constrictive bronchiolitis" is a striking lesion seen in a minority of smokers, and in some other lung diseases. It's dense fibrosis around bronchioles with serious compromise of the lumens.

      Emphysema causes obstruction to air flow because loss of the lung's elastic recoil allows small airways to collapse at the beginning of expiration. We all lose some elasticity as we age, but smokers and people who are alpha-1 antitrypsin deficient lose it much more, and also have some destruction of their septa, which is not part of normal aging.

      NOTE: Some people include all asthma cases as COPD, but regular asthma has a much better prognosis. Today, even chronic "asthmatic bronchitis" is distinguished from other forms of chronic bronchitis, which are much more lethal: NEJM 317: 1309, 1987.

    Both emphysema and chronic bronchitis are most commonly caused by cigaret smoking. Most smokers with one have the other, too.

      Smokers should be prepared for:

      • tobacco pigment in the lungs (brown stuff)
      • carbon pigment in the lungs ("anthracosis"; more than non-smokers)
      • loss of ciliary motility (maybe; these people don't get problems so severe as people with congenital immotile cilia do)
      • goblet cell proliferation in remaining columnar epithelium
      • hypertrophy and hyperplasia of mucous glands, with much more mucus (Chest 130: 1102, 2006)
      • thickening of the respiratory epithelial basement membrane ("subepithelial collagen deposition")
      • increased numbers of polys in the lungs (about four times as many in the mucosa: J. Clin. Path. 60: 907, 2007)
      • increased numbers of alveolar macrophages (x6 or so)
      • impaired ability of alveolar macrophage to function usefully
      • increased neutrophil and macrophage elastase production and release
      • impaired ability of alveolar macrophage to function usefully
      • squamous metaplasia of respiratory epithelium (contrary to what others may have told you, this is the exception rather than the rule)
      • loss of elasticity of alveolar walls
      • eventual destruction of alveolar walls

      Robbins's past estimate of "10,000 to 20,000 deaths in the U.S." yearly due to COPD is much too low. COPD probably contributes in a major way to around 100,000.

      * Supposedly the neuropathies seen in these patients are due to hypoxemia itself.

      * Not a trivial problem -- advising the COPD patient about air travel: Ann. Int. Med. 111: 362, 1989.

EMPHYSEMA

Emphysema
Lung pathology series
Dr. Warnock's Collection

Emphysema
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery

Emphysema I
From Chile
In Spanish

Emphysema II
From Chile
In Spanish

Emphysema
Good blebs
WebPath

Emphysema
Supposedly centrilobular
WebPath

"Types of emphysema"
Lung pathology series
Dr. Warnock's Collection

Centrilobular emphysema
Formalin-inflated lung
KU Collection

Emphysema
Supposedly centrilobular
WebPath

Emphysema
Trashed, overstretched alveoli
WebPath