Professor
Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week
of 8th September 2016 (#59)
University
of Notre Dame Australia (Fremantle Campus)
Occasional Editorial Comment
I urge you to read the Weekly Review through the above
blog link. It is better formatted and additionally allows the determination of
the number of weekly readers.
Must Read Articles
None
Articles Recommended for Medical Students
Perspective
Scrub
Typhus — Scientific Neglect, Ever-Widening Impact
Detection
of scrub typhus, a vectorborne infectious disease, in Chile and Africa
highlights the fact that we have heretofore paid too little attention to this
systemic, life-threatening disease and have developed too little relevant
expertise.
ORIGINAL ARTICLE
BRIEF REPORT
Endemic
Scrub Typhus in South America
Scrub
typhus, caused by Orientia tsutsugamushi, has been thought to be
geographically restricted to the “tsutsugamushi triangle” in the Asia–Pacific
region. In this report, a potential focus in southern Chile is identified.
I enjoy the word “tsutsugamushi” (from the Japanese tsutsuga "illness"
and mushi "insect") which to me has the same fascination as “dysdiadochokinesis”
(from the Greek dys “bad” , diadocho “succeeding”, kinesis “movement,” a word which
every medical student seems to be able to remember.
For any student interested in infectious disease,
tropical medicine in particular, and climate change, scrub typhus biology is perhaps
a career choice to explore. Basic
research is wanting and a significant discovery could produce a major benefit
to humanity. Also funding is likely to be available in the future for an
illness which is changing geographically due to global climate change.
The article describes the recent appearance of Orientia
tsutsugamushi (previously classified as a rickettsia and still studied by
rickettsiologists who are few and far between) in three patients on a small
island (Chiloé Island) off the southern coast of Chile. How this organism reached
this island is a matter of speculation. Did it arrive from mainland Chile where
it has not been previously described, or was it carried by birds from the
tsutsugamushi triangle? The article also provides excellent pictures of the
initial necrotic bite site ulcer (eschar) (Figure 1).
This rickettsial bacterium is transmitted by the bites
of larval mites (chiggers) which live on rodents. It occurs widely in rural
settings in Asia (in the tsutsugamushi triangle with Australia at the southern
tip of the triangle) and is a potential risk in tropical Northern Australia. It
has also spread northward into China.
The following have been extracted from the Perspective
and describe the disease clearly:
1.
Scrub
typhus, a systemic, life-threatening disease with an enormous incidence in Asia
and the islands of the Pacific and Indian Oceans, remains remarkably neglected.
2.
Infection
with Orientia tsutsugamushi, the causal agent, classically begins
with the appearance of an eschar at the site of mite feeding and enlargement of
the draining lymph nodes, followed by fever, headache, myalgia, and
gastrointestinal symptoms. In severe cases, the illness can progress to the
development of interstitial pneumonia, acute respiratory distress syndrome,
meningoencephalitis, acute kidney injury, or disseminated intravascular
coagulation, causing death in 7% or more of patients unless they are treated
sufficiently early in the course of illness with doxycycline, azithromycin, or
somewhat less effectively, chloramphenicol.
3.
O.
tsutsugamushi is an obligate intracellular bacterium that is maintained in
nature transovarially in mites. It’s essential to understand that the mite
(chigger) is both the vector and the reservoir. Rodents become infected
with O. tsutsugamushi and maintain the infection for a prolonged
period.
4.
Studies
of febrile patients in Asia reveal that scrub typhus and murine typhus are often
at least as prevalent as malaria, dengue, and other arboviruses. Previous
estimates of 1 million cases of scrub typhus annually would most likely be
revised upward by accurate incidence data on the current re-emergence in Asia.
ORIGINAL ARTICLE
CPAP
for Prevention of Cardiovascular Events in Obstructive Sleep Apnea
In
a randomized trial, over 2700 patients with obstructive sleep apnea and
cardiovascular disease were assigned to CPAP plus usual care or to usual care
alone. At a mean of 3.7 years, the rate of adverse cardiovascular events did
not differ significantly between the groups.
EDITORIAL
Cardiovascular
Events in Obstructive Sleep Apnea — Can CPAP Therapy SAVE Lives?
I have many problems with this article but particularly
the conclusions. The study was conducted through the Institute for Sleep Health,
Flinders University, and other institutions in Adelaide and South-East
Asia. Approximately 63% of the patients
in the study were from South-East Asian centres. Employing 89 centres in seven
countries makes standardization of therapy in the study extremely difficult.
This is a multinational, randomized (CPAP or usual
care), parallel-group, with open-label trial with blinded end-point assessment. The study attempts to ascertain the efficacy
of CPAP in patients with established cardiovascular disease (secondary
prevention study). The primary composite end point was death from
cardiovascular causes, myocardial infarction, stroke, or hospitalization for
unstable angina, heart failure, or transient ischemic attack. Secondary end
points included other cardiovascular outcomes, health-related quality of life,
snoring symptoms, daytime sleepiness, and mood.
The overall results indicated that CPAP did not prevent
the primary end-points in patients with moderate-to-severe sleep apnoea and
established cardiovascular disease over those patients treated with usual care. Conversely, there was a marked improvement in
secondary outcomes (Table 3). These included significant improvements in
quality of life (daytime sleepiness, anxiety and depression, physical and
mental improvement) which were not emphasised strongly enough in the results
and discussion sections of the article.
The following problems with the study are:
1. This
is a secondary prevention study which was undertaken because the number of
patients needed to complete a primary prevention study would have been too
large.
2. The
authors appear to neglect the significant symptomatic improvement in the
patients. They do not seriously consider improvement in quality of life a
legitimate indication for CPAP in this patient group. This causes me to wonder how many of the individuals
writing the manuscript actually treat patients.
3. The
technical use of CPAP overall was very poor. The mean duration of CPAP
adherence was only 3.3 hours per night, only half of the usual sleep time. Thus CPAP was probably used only in the first
half of the nightly sleep. It was noted in the Editorial that “in many of the
trial patients, CPAP may not have been in use during rapid-eye-movement (REM)
sleep, the sleep stage that predominates in the early morning hours. This is a
concern because apneic or hypopneic events that occur during REM sleep are
longer, with greater oxygen desaturation, than those that occur during non-REM
sleep; moreover, events that occur during REM sleep have a significantly
stronger association with hypertension.” It was further noted in a sub-group
analysis using far fewer numbers (making it difficult to validly interpret many
of the results) that there was an improvement in one primary outcome,
particularly a reduction in the risk in cerebrovascular events (p=0.02). Thus,
this study needs to be repeated in which CPAP adherence should include the
early morning hours with probably 5-6 hours of CPAP use a minimum.
4. It
is possible that once the patient has established significant symptomatic
cardiovascular pathology, CPAP may not improve the primary outcomes, but I seriously
doubt this based on the study.
5. The
exclusion criteria should be carefully analysed, as patients with severe sleep
apnoea were excluded. These patients may well have had better primary outcomes.
This article was probably published because of the time
and effort spent by the investigators, the cost and the multinational nature of
the study. Further, this was a difficult study to perform with an adequate
number of patients, and as such the ideal study is unlikely to be undertaken in
the near future.
Recommended
learning:
1. Review
the causes, clinical manifestations and management of obstructive sleep apnoea
in adults and children.
2. Review
the use of CPAP in clinical medicine.
CLINICAL PRACTICE
Acute
Sinusitis in Adult
Acute
bacterial sinusitis — purulent nasal discharge and nasal obstruction; facial
pain, pressure, or fullness; or both — persists for 10 days or more with no
improvement or worsens within 10 days after improvement. Watchful waiting and
antibiotic therapy are described.
This is a Clinical Practice article discussing acute
sinusitis in adults. At a minimum, the Clinical Problem and the Key Clinical
Points should be read, as well as a review of the algorithm for the diagnosis
and initial management of acute sinusitis in adults (Figure 1).
As stated by the author: The natural history of acute sinusitis in adults is very favorable;
approximately 85% of persons have a reduction or resolution of symptoms within
7 to 15 days without antibiotic therapy. Nonetheless, antibiotics are
prescribed for 84 to 91% of patients with acute sinusitis that is diagnosed in
emergency departments and outpatient settings.
Recommended
learning: Diagnosis and management of acute sinusitis
IMAGES IN CLINICAL MEDICINE
Kerion
— A Boggy Lump
A
13-year-old girl presented with a slowly enlarging, painful swelling of the
scalp. She had received several courses of empirical oral antibiotics, without
improvement. On examination, there was an erythematous, mildly tender, boggy
swelling overlying her occiput.
A kerion is an erythematous, boggy, suppuratives
lesion, usually on the scalp in children, associated with ringworm infection.
This is caused by either Trichophyton or Microsporum infection of the scalp and
skin follicles (tinea capitis). The excessive inflammatory response to the
fungus results in abscess formation with superficial pustules (secondary
bacterial infection), hair loss, and multiple black spots which are broken
hairs in the follicle. Typically “ring worm” fungal infection is confined to
the stratum corneum of the epidermis.
Kerion should be treated with antifungal therapy such as griseofulvin or
fluconazole. Alopecia may be permanent.
IMAGES IN CLINICAL MEDICINE
Generalized
Granuloma Annulare Associated with Diabetes Mellitus
A
64-year-old man presented with widespread, erythematous-to-violaceous papules
that were distributed symmetrically on his trunk, arms, and legs. Skin biopsy
revealed palisading granulomatous inflammation that surrounded degenerating
collagen within the dermis.
Granuloma annulare can be localized (more common) or
generalized (uncommon). It is manifested by erythematous plaques which form a
ring shaped lesion with more normal skin in the centre. The lesions are
asymptomatic, flare in the summer, and are generally self-limiting but may take
up to two years to spontaneously resolve. These lesions can occur in children
and adults. The histology of the lesion is a dermal granuloma with palisading fibrohistiocytic
and spindle cells surrounding an area of necrotic collagen. The number of giant
cells is variable. The cause is unknown, though it is occasional associated
with diabetes mellitus as in this case.
Recommended
learning: Review the skin lesions erythema multiforme, erythema
marginatum, granuloma annulare, erythema annulare, erythema chronica migrans,
discoid LE.
CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Case
27-2016 — A 71-Year-Old Woman with Müllerian Carcinoma, Fever, Fatigue, and
Myalgias
A
71-year-old woman with müllerian carcinoma was admitted to the hospital because
of fever, fatigue, and myalgias 3.5 weeks after extensive cytoreductive
surgery. Anorexia, abdominal pain, and bloating had developed 1 day earlier.
Diagnostic studies were performed.
The patient presented with fever, fatigue, myalgia,
abdominal pain and alternating constipation and diarrhoea 19 days after
cytoreductive surgical therapy for extensive metastatic müllerian carcinoma. There is a detailed discussion of the
differential diagnosis of late post-operative fever. For those with a specific
interest in pathology, the discussion of müllerian carcinoma and its management
makes for interesting reading.
Recommended
learning: Review the causes of post-operative fever at specific
time periods after surgery.
Important Articles Related to Mechanisms of Disease and
Translational Research
None
Other Articles which should interest medical students
REVIEW ARTICLE
The
Primary Outcome Is Positive — Is That Good Enough?
When a clinical trial reaches its
primary outcome, several issues must be considered before a clinical message is
drawn. These issues are reviewed in this article.
This is another article in the Clinical Trials series.
The hyperlinks should be stored with the others in this series for review in
the future when necessary.
New Pharmacological Therapies
None
Other articles which may be of interest to certain students
ORIGINAL ARTICLE
Adalimumab
in Patients with Active Noninfectious Uveitis
This
phase 3 trial showed that persons with noninfectious uveitis who received
adalimumab were more likely to have serious adverse events and less likely to
have ophthalmic inflammation, uveitic flare, or visual impairment than were
those who received placebo
ORIGINAL ARTICLE
Cord-Blood
Transplantation in Patients with Minimal Residual Disease (for acute leukaemia
of myelodysplastic syndrome)
Patients
with minimal residual disease who received a cord-blood transplant had a higher
probability of survival than those receiving a transplant from mismatched
unrelated donors and a lower risk of relapse than those receiving a transplant
from matched or mismatched unrelated donors.
