Professor
Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week
of 1st September 2016 (#58)
University
of Notre Dame Australia (Fremantle Campus)
Occasional Editorial Comment
None
Must Read Articles
REVIEW ARTICLE
Early-Life
Origins of Chronic Obstructive Pulmonary Disease
The
conventional thinking about COPD is that exposures in adult life, such as
smoking, lead to a low FEV1:FVC ratio, the physiological hallmark of COPD. In
this review, the effect of early-life exposures on the lung that could lead to
expiratory airflow limitation is reviewed.
The causes of chronic obstructive pulmonary disease
(COPD) and the concept that multiple triggers can lead to this heterogeneous
disorder is discussed in this article.
COPD is characterised by irreversibly airway obstruction with an
abnormally low FEV1 and an FEV1/FVC ratio of less than 0.7. The classic cause of
COPD is cigarette and biomass smoke associated with emphysema and chronic
bronchitis and leading to neutrophil and CD8 mediated pulmonary inflammation.
The evolving concept is best illustrated in Figure
1. This suggests that in classical COPD,
pulmonary function remains normal (FEV1 at 100% of predicted) until around the
age of 30 years and then progressively declines with continued smoking ultimately
reaching an FEV1 less than 80% of predicted around the ages of 50–60 years.
The newer concept suggests that some infants are born
with a persistently reduced FEV1 due to a variety of prenatal influences:
1. Genetic
factors: Up to 26 loci (SNPs) may explain up to 7.5% of the additive polygenic
variance for the FEV1: FVC ratio and 3.4% of the FEV1 reduction.
2. Maternal
smoking: In animal models, reduction in birth FEV1 can be produced by intrauterine
nicotine exposure alone. Thus, e-cigarettes which contain purified nicotine,
may not be a healthy alternative to cigarette smoking.
3. Bronchopulmonary
dysplasia associated with prematurity and early oxygen requirements.
4. Intrauterine
growth retardation.
5. Malnourished
populations associated with maternal micronutrient deficiency.
Further risk factors throughout childhood and
adolescence can lead to an early rapid decline in FEV1 through the age of six
years and then a slower progressive decline to reach FEV1 levels diagnostic of
COPD by the age of 60 years (Figure 1).
Factors in this age range which contribute to COPD
development include:
1. Radiologically
defined pneumonia before the age of 3 years (a major contributor). Some
children with adenovirus serotypes 3, 7, and 21 may develop more severe
long-term sequelae including bronchiolitis obliterans and bronchiectasis.
2. Air
pollution. Data for the LA basin showed that a reduction in the number of
inhaled smaller microparticles and nitrogen dioxide resulted in fewer with an
FEV1 less than 0.8 over the 13 year study period.
3. Persistent
childhood asthma (Figure 3-data from the Melbourne Asthma Study).
4. Active
smoking during adolescence.
Students should carefully read this article which is
full of specific information and develop a scientific approach to the
prevention and management of COPD.
Articles Recommended for Medical Students
CLINICAL PROBLEM-SOLVING
Tip
of the Tongue
A
65-year-old woman with a history of HIV infection, hypertension, and
hyperlipidemia had a 1-week history of cough with pink sputum and mild
shortness of breath on exertion, but no fever, chills, night sweats,
rhinorrhea, or nasal congestion.
This is 65 year old smoker with AIDS (CD4 count less
than 200 cells/cub. mm.) who presents with new-onset haemoptysis and a lung
mass. The provisional diagnosis should be obvious to a medical student. However,
in an immunosuppressed patient with AIDS, the immediate tendency may be to focus
on infection. The patient also had brain stem cranial nerve involvement which
led to an excellent discussion on leptomeningeal carcinomatosis.
Recommended
learning: Review the causes and investigations of a patient
presenting with dysarthria in varying age groups.
ORIGINAL ARTICLE
Safety
of Adding Salmeterol to Fluticasone Propionate in Children with Asthma (1)
This
large trial involving children with asthma examined whether the addition of a
long-acting beta-agonist to current therapy with inhaled glucocorticoids
affected asthma control in children. The primary safety end point was within
the prespecified noninferiority margin.
EDITORIAL
Safety
of Long-Acting Beta-Agonists in Children with Asthma
ORIGINAL ARTICLE
Serious
Asthma Events with Budesonide plus Formoterol vs. Budesonide Alone (2)
In
adolescents and adults with moderate-to-severe asthma, the addition of
formoterol to inhaled glucocorticoids was associated with a lower risk of
asthma exacerbations than that with glucocorticoids alone and with a similar
risk of serious asthma-related events.
The two articles and the Editorial discuss the use of
long-acting agonists (LABA) in childhood asthma (1) and in patients older than
12 years with serious asthma (2). The Editorial summarises the strengths and
weaknesses of both studies but focuses on childhood asthma.
The results indicate that if standard prophylactic
corticosteroids fail to control asthma (unusual), rather than increasing the
corticosteroid dosage, it appears to be acceptable to add a LABA to the inhaled
corticosteroid. Serious adverse effects, such as the rare event of sudden death,
were not seen in these studies.
Several important points were extracted verbatim from
the Editorial:
1. Exacerbations
are related to asthma-control status, history of exacerbations, environmental
triggers, and seasonal, genetic, and immunologic modifying risks.
2. Predominant
causes of asthma-related death are lack of access to health care (45% of
the participants had not attempted to seek professional help), lack of personal
action plans, underuse of glucocorticoids, overuse or inappropriate use of bronchodilators,
underestimation of asthma severity by treating doctors and by parents, lack of
objective measures of airway obstruction, and nonadherence to the regimen,
including drug and alcohol use by caretakers.
3. Particularly
in children and young people, the poor recognition of the risk of an adverse
outcome was an important avoidable factor.
4. Most
children will have their asthma controlled by low-dose inhaled glucocorticoids
if taken regularly through an appropriate device.
5. Monotherapy
with a LABA in a child should be considered medical negligence.
6. For
the unusual child with asthma who needs more than low-dose inhaled
glucocorticoids to control the disease or who has persistent, objectively
documented, variable airflow obstruction, the present trial provides reassuring
evidence that combination inhalers containing a LABA and an inhaled
glucocorticoid are safe.
IMAGES IN CLINICAL MEDICINE
Emphysematous
Prostatitis
A
42-year-old man with diabetes presented to the ED with severe dysuria and
incontinence. Laboratory studies were notable for pyuria, leukocytosis,
elevated C-reactive protein, and hyperglycemia. Radiography showed an atypical
focus of gas accumulation behind the right pubic ramus.
While the most common cause of bacterial prostatitis is
E. coli. In the rare patient with emphysematous prostatitis
(occurring predominantly in diabetic and immunosuppressed patients), the most
common cause is K. pneumoniae.
Emphysematous pyelonephritis, again more common in diabetics,
is usually due to E. coli or K .pneumonia. In more recent
reports, successful management has been achieved with systemic antibiotics
together with percutaneous catheter drainage of gas and purulent material, as
well as relief of urinary tract obstruction (if present) (UpToDate). The previous
standard treatment, which is still occasionally required, is total nephrectomy
and drainage.
Recommended
learning: Review the causes, presentations and management of
acute and chronic prostatitis.
ORIGINAL ARTICLE
Antiretroviral
Therapy for the Prevention of HIV-1 Transmission
In
this report involving 1763 HIV-1 serodiscordant couples, the suppression of
HIV-1 in the infected partner significantly decreased the transmission of
genetically linked HIV-1 to the uninfected partner.
The most common mode of HIV infection world-wide is
sexual transmission.
The aim of this study was to determine if treatment of
HIV in the infected partner leads to fewer infections in the uninfected
partner. The two study groups of infected patients were either those with CD4
counts between 350 – 550 /cub.mm (early treatment group ) or those followed and
treated when the CD4 count fell below 250 on two occasions or the patient
developed an AIDS-defining illness (extended treatment group).
Genetic analysis of the HIV was determined initially in
the infected partner at onset of the study and when HIV infection occurred in
the previously HIV negative partner. A similar HIV genetic profile indicated transmission
from the infected to the uninfected partner, while differing genetic profiles indicated
that the previously uninfected partner received the HIV from another infected source.
1763 couples were enrolled in the study (see Figure 1).
Seventy eight (78) HIV
infections were demonstrated in the previously uninfected partners over a five
year study period. Seventy two (72) of the new infections were able to be
genotyped.
The data indicate that genetically-linked HIV in the
early treatment group was reduced by 93% when compared with the extended treatment
group. Most of the infections that occurred in the early treatment group (82%)
were not genetically linked, while in the extended treatment group 22% were not
genetically linked.
In the early treatment group, most HIV infections
occurred by a second infected partner, although there were a few with similar
genotypes probably indicating inadequate or non-compliance with medication. In the extended treatment group, 78% of
infections were linked and 22% were unlinked. Thus early prophylactic treatment
of the HIV positive partner resulted in a marked reduction in HIV infection in
the uninfected partner and was completely eliminated if the HIV infection was
stably supressed in the early treatment partner.
Important Articles Related to Mechanisms of Disease and
Translational Research
CLINICAL IMPLICATIONS OF BASIC RESEARCH
Muscling
In on Cancer
Investigators
recently described a study of mouse models of cancer, in which they found that
contracting muscle fibers synthesize an anticancer myokine, interleukin-6.
Hippocrates
is reported to have said, “Walking is man’s best medicine.” Regular exercise,
including daily brisk walking, is associated with a lower risk of several
cancers and with lower risks of tumor recurrence and death among survivors,
particularly of colorectal and breast cancers. Data suggest a potential
dose-dependent benefit of exercise against colon cancer and possibly
postmenopausal breast cancer. People with the highest exercise loads have a 40%
lower cancer-related mortality than the general population.
Previous studies have indicated that muscle fibres
contracting during exercise release myokines that lead to apoptosis in breast
and colon cancer cells. In the currently reviewed study in Cell Metab. 2016,
the researchers demonstrated in exercising mice with melanoma, liver and lung
cancer that IL-6 (muscle origin) and epinephrine were released post-exercise. These factors could have been responsible for
increased mobilization of NK cells into the tumours and enhanced expression of
NK ligands on the tumour cells leading to their destruction by the NK cells.
This provides further evidence that for patients with a
malignancy, exercise can only help other therapies in combating the tumour.
Recommended
learning: Review the evidence that exercise is beneficial to
your health.
Other Articles which should interest medical students
ORIGINAL ARTICLE
Mutations
Associated with Acquired Resistance to PD-1 Blockade in Melanoma
Whole-exome
sequencing was performed on four patients' tumors before exposure to
pembrolizumab and after disease progression following a response to treatment.
Acquired mutations involving antigen presentation and interferon response were
noted.
EDITORIAL
Unmasking
PD-1 Resistance by Next-Generation Sequencing
PD-L1 is a ligand on the surface of cells which stops
them being destroyed by T cells. T cells possess PD-1 on their surface and when
this reacts with PD-L1 ligand, the T cells are inactivated and unable to
destroy the cell. This is a normal mechanism of tolerance to protect cells from
destruction by circulating T cells.
However, when tumour cells express PD-L1 ligand on their surface, they evade
destruction by T cells. Pembrolizumab is a humanized monoclonal antibody (a
form of check-point therapy) that binds to PD-1 on the surface of T cells,
stops T cell inactivation by PD-L1 on the surface of the tumour cell, and
allows the T cell to destroy the tumour cell.
This drug is
being employed effectively in the treatment of metastatic melanoma (up to 75%
objective responses) and more recently in some forms of lung cancer. This is
the drug has been extremely effective in the short-term treatment of metastatic
melanoma in President Jimmy Carter (https://www.mskcc.org/blog/understanding-jimmy-carter-s-surprise-turnaround-conversation-jedd-wolchok).
The study describes in detail four patients with
metastatic melanoma who responded initially to Pembrolizumab but who
subsequently developed resistance to the drug. Each patient had biopsies
studied before therapy and then after recurrence. Whole-exome sequencing was
carried out on all samples, as well as immunohistochemical analyses for CD8
positive T cells, PD-L1 expression, and melanoma cell markers. In three of the
patients, mechanisms of resistance to immune destruction were suggested. In two
patients loss-of-function mutations in the genes encoding
interferon-receptor-associated Janus kinase 1 and Janus kinase 2 were
found. This mutation lead to lack of
response of the tumour cell to interferon. In the third case a truncating
mutation of b-2-microglobulin (necessary to form the extra-membrane chain of
the class I MHC) was found. Absence of functional class I MHC on the surface of
the tumour cell would allow it to avoid destruction by cytotoxic CD8 positive T
cells.
This study involved an enormous effort by many
investigators and provides evidence for a variety of molecular mechanisms of
acquired resistance to pembrolizumab in three patients with metastatic
melanoma. In the Discussion section of the article, further conventional mechanisms
are described which may account for tumour resistance.
Recommended
learning: Review the basic mechanisms whereby tumours can escape
immune detection and subsequent destruction.
IMAGES IN CLINICAL MEDICINE
Pneumorrhachis,
Pneumothorax, and Subcutaneous Emphysema
A 65-year-old man was admitted for adjuvant radiotherapy after a previous tumor mass reduction and stabilizing spinal surgery for a synovial sarcoma. Ballooning of the left paravertebral area, which increased when the Valsalva maneuver was performed, is shown in a video.
The very interesting series of CT scans and the video
should be reviewed. This was a first for me as well as learning the definition
of pneumorrhachis (air in the intraspinal space where it can be extradural or
intradural). A previous review discusses this event (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1602196/ )
which can be minor and fairly common or major and uncommon (as in this case).
REVIEW ARTICLE
THE CHANGING FACE OF CLINICAL TRIALS
The
Primary Outcome Fails — What Next?
When
the primary outcome of a clinical trial fails to reach its prespecified end point,
can any clinically meaningful information still be derived from it? This review
article addresses that question.
This is another article in the Clinical Trials series
which should be stored with all previous articles in your data base for further
use. All of these articles will be useful when UNDA embarks on the MD in 2017
and will help in the reviewing of articles that pertain to clinical trials and
their design.
New Pharmacological Therapies
None
