On the death of Infants

The recent controversy and allegations over the infant death in the BC Roy Post-Graduate Institute of Paediatric Sciences demands that we examine the issue critically. Every death is lamentable but we should also recognize that every death is not preventable unless action is taken in a timely manner. Only by examining what went wrong we can begin to rectify them.

Image Courtesy : Rana2030

Various reports from the media state that initially 12 infants died within a period of 48 hours and later 3 more deaths occurred in the third day taking the toll to 17 infants in 3 days (1, 2).

The role of the media here calls for criticism. What the media is trying to report is the rate of infant death but it is meaningless unless we know how many infants were admitted in the hospital in these days. The media failed to mention the prevailing infant mortality rate in the hospital. Was the death rate in these 3 days significantly higher than the prevailing death rate? Without this crucial information any reporting of the incident only helps in polarizing and sensationalizing the issue and is of no real help.

Let us look at some data. I couldn’t find data specifically for the hospital in question but data was available for another hospital in the city (3). Although it is not ideal, we can use it as a proxy for the absent data from the hospital in question. A total of 1216 infants were admitted to a tertiary care hospital in a year. 286 died, making the infant mortality rate 23.52%/year which is pretty high. Consider this, if 20 infants were admitted everyday for 3 days, we can expect that a total of 14 would have died. This example of course has several limitations. For starters we don’t know how many infants were actually admitted to the hospital in question. We don’t know the prevailing infant mortality in the hospital. It may so happen babies who were very sick and couldn’t be managed elsewhere were referred to the BC Roy hospital as it is a specialized hospital. What I want to say with this example is that we can’t draw any meaningful conclusion from what the media reported though it is a sensitive issue on which we should have an informed opinion.

The knee-jerk response of the government is also unfortunate. The solution that the government proposes is opening of more Sick Newborn Care Units all across the state. This is commendable but we should realize that this constitutes what the public health doctors term as secondary prevention, meaning taking early action after the disease/event has already occurred. A better way is primary prevention which aims at preventing the disease/event from happening at the first place. Primary prevention demands long term commitment from the all the parties involved. Let us look at the common causes of hospitalized infant deaths in the city – septicemia, birth asphyxia, prematurity, acute respiratory tract infections, meningitis, congenital anomalies, congenital heart defects etc (3).

If we examine the risk factors for the causes of infant death, we can see that many of them are preventable. For example higher paternal education significantly decreases the risk of birth asphyxia. Low birth weight is an established risk factor for birth asphyxia and chronic mater malnutrition is one of the major causes of low birth and prematurity. Poor prenatal care, low socioeconomic status, low birth weight and birth asphyxia itself are causes of septicemia in infants (4, 5, 6).

There are few factors which if controlled will lead to a decreased incidence of the diseases affecting neonates and by extension a reduction in the infant deaths. Maternal nutrition, proper antenatal checkups, improvement in the socioeconomic and living standards of the mothers, proper education of the parents are some of the areas where improvement will lead to a better outcome. This, in conjunction with improved secondary prevention strategies will hopefully prevent further occurrences of such incidences in future.

Conflict of interest – I had attended few lectures of Dr. DK Paul, Superintendent of BC Roy Post-Graduate Institute of Paediatric Sciences when he was posted at my college.

References:

1. MARCUS DAM. Four more crib deaths in Kolkata hospital, 12 in Bardhaman hospital. The Hindu. October 29, 2011
2. Infant deaths in B C Roy hospital again. The Telegraph. 26th October, 2011.
3. Roy, RabindraNath. (2008) Mortality pattern of hospitalized children in a tertiary care hospital of Kolkata. Indian Journal of Community Medicine, 33(3), 187
4. Lee, A. CC. (2008-05-01) Risk Factors for Neonatal Mortality Due to Birth Asphyxia in Southern Nepal: A Prospective, Community-Based Cohort Study. PEDIATRICS, 121(5), e1381-e1390.
5. Anderson-Berry AL. Neonatal Sepsis. Medscape Reference.
6. Paul VK, Singh M, Sundaram KR, & Deorari AK. (1997) Correlates of mortality among hospital-born neonates with birth asphyxia. The National medical journal of India, 10(2), 54-7.

Outbreak of viral encephalitis in Bihar, India

An outbreak of viral encephalitis is ravaging the childrenof Magadh division in Bihar India. This is the second wave of encephalitis that has hit the state after the rainy season with 383 children affected and 82 lives lost. The local health authorities are ill equipped to handle such an epidemic and Bihar being one of the poorest states of India does not help much. Conveniently the local media has given it scant or no coverage.

Image courtesy: The Hindu

 Suspected causative agents

It appears that more than one microorganism is responsible for the outbreak with the Japanese encephalitis virus (JEV) being the prime suspect. It is estimated that at least one third of the cases are caused by JEV which is endemic in the region. JEV, a flavivirus, consists of eight virus species and two subtype viruses. Japanese encephalitis is a zoonotic disease with the zoonotic cycle affecting mosquitoes and pigs and/or water birds. Humans are dead end hosts and become infected accidentally. The major vector implicated in transmission to humans is the mosquito Culex tritaeniorhynchus, breeding mainly in rice paddies. Both rice paddies and pigs are abundant in rural Bihar, perpetuating the epidemic.

JEV has an incubation period of 5 to 15 days with the average incubation period being 6-8 days. There is usually a prodromal period at the onset characterized by nausea, vomiting, diarrhea, fever and headache. The prodromal period, which can last for several days, is followed by higher mental functional abnormalities ranging from mild confusion to coma. Seizures are common in children. Tremors and other movement disorders may occur. Acute flaccid paralysis resembling poliomyelitis may also occur. The fever generally disappears by the second week of the disease followed by the onset of extrapyramidal symptoms like chorea.

On examination, hypertonia and hyperreflexia may be present. There may be cranial nerve involvement like facial palsy etc. Parkinson like extrapyramidal features may be present. Mortality in resource poor settings is about 35%.

In ProMED-mail, an internet based outbreak reporting system of the International Society for Infectious Diseases, enterovirus infection has also been suggested as a plausible etiologic agent. However there is no evidence available at present for an enteroviral cause.

Failure of Policy?

Following an outbreak of JE in 2009 in the Bodh Gaya division of Bihar, a massive vaccination campaign was launched in that division and no further cases of JE were reported. Inexplicably such vaccination campaigns were not organized in other divisions of the state. Result – fresh outbreak in another division (Magadh).

The local hospital is also in shambles with water and power shortages and the only ventilator lying useless.

Mackenzie, J., Gubler, D., & Petersen, L. (2004). Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses Nature Medicine, 10 (12s) DOI: 10.1038/nm1144

Actionable evidence: Injectable contraceptives increase the risk of HIV infection

I was thinking of a new category of posts which I would be calling actionable evidence. Actionable evidence is that evidence which you can immediately put into practice; these are of direct clinical relevance. So to start this off I have selected a very important study that came out in the Lancet Infectious Diseases titled “Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study”. Here is the main outcome of the study –

Risk of HIV acquisition in women

	Hazard ratio (95% CI) Adjusted Cox proportional hazards regression analysis	Hazard ratio (95% CI) Adjusted marginal structural models analysis
Any Hormonal Contraception	1.98 (1.06-3.68)*	1.84 (0.98-3.47)
Injectable	2.05 (1.04-4.04)*	2.19 (1.01-4.74)*
Oral	1.80 (0.55-5.82)	1.63 (0.47-5.66)
	*significant

Risk of transmission from women to men

	Hazard ratio (95% CI) Adjusted Cox proportional hazards regression analysis	Hazard ratio (95% CI) Adjusted marginal structural models analysis
Any Hormonal Contraception	1.97 (1.12-3.45)*	2.05 (1.12-3.74)*
Injectable	1.95 (1.06-3.58)*	3.01 (1.47-6.16)*
Oral	2.09 (0.75-5.84)	2.35 (0.79-6.95)
	*significant

Recommendation of the authors - Women should be counseled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, especially injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk.

Comment –

Injectable contraceptives are used as suitable contraceptive method by many women. It has the advantage of ease of use. For example, DMPA (depot medroxyprogestrone acetate), one of the injectable contraceptives, can be taken at 3 monthly intervals. You don’t have to worry about contraceptives during these 3 months which is a problem with the oral pill, which has to be taken daily and one might forget to take it.

The study was of prospective cohort design with African serodiscordant (one partner with HIV infection and other partner free from infection) couples, though the majority of the data is taken secondarily from a randomized control trial. Basically the authors recruited HIV serodiscordant couples and subsequently they tested the HIV uninfected partner to see if they are getting infected. After doing this, they compared if the rate of infection  was more in seronegative subjects who were using hormonal contraceptives or in case of male subjects whose female partners were using hormonal contraceptives with those who were not using hormonal contraceptives. They followed the subjects for 24 months with mean follow up in seronegative women being 18 months and mean follow up of 18.7 months for seronegative men.

Overall this is a well conducted study, though there are few issues related to the methods. Firstly, the contraceptive use was self reported. Secondly, the use of injectable hormonal contraception was quite low among the participants but the study was adequately powered. Thirdly, the incidence of HIV infection was quite low. Fourthly, it is not clear to me whether the assessors were blinded to the nature of contraception use by the participants.

Before you ask the obvious, the authors controlled for the number of unprotected sexual intercourse. Even after controlling for unprotected sexual intercourse, injectable hormonal contraceptives significantly increased the risk of HIV infection. This suggests that something other than just unsafe sex is at play here.

Bottom line – Injectable hormonal contraceptives might increase the risk of HIV infection, evidence from observational study. All women using injectable hormonal contraceptives should be counseled to use condoms during intercourse to prevent HIV infection. Randomized controlled trial needed to see if the association holds.

Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E, de Bruyn G, Nakku-Joloba E, Ngure K, Kiarie J, Coombs RW, Baeten JM, & for the Partners in Prevention HSV/HIV Transmission Study Team (2011). Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. The Lancet infectious diseases PMID: 21975269

Hepatosplenomegaly with fever in a child

Yesterday I got into a discussion with one of my friends about a case. He had examined a 7 year old male child who presented with fever for the last 7 days. The fever was of mild grade, continuous in type. The fever was not associated with any chills, rigor or sweating. There were no complaints of headache, vomiting, visual disturbance or convulsions. There was no history suggestive of any upper respiratory tract infection , urinary tract infection or any rash. The child complained of dark colored stool but on further inquiry it was not judged to be melaena. There was a history of mild abdominal pain, non colicky and possibly dull aching in nature (one can only get so much out of a child).

On examination the vitals were normal. There was mild, soft tender hepatomegaly and mild splenomegaly. There were no visible veins over abdomen. There was no lymphadenopathy. There was no jaundice. Rest of the examination findings were within normal limits.

Hepatomegaly - from NIH

Based on the history and examination findings the differential diagnosis consisted of

·        Acute viral hepatitis

·        Acute leukemia

·        Malaria

·        Acute hemolysis

·        Enteric fever

·        Lymphoma

·        Disseminated tuberculosis

My friend was of the opinion that the child had malaria. I disagreed.  My argument was that for a child to have malaria with hepatosplenomegaly, the duration needs to be pretty long. More over there is a correlation between jaundice and hepatomegaly in patients of malaria (1). Here the child did not have jaundice. I thought that enteric fever or acute leukaemia fits better. Mind you, neither of us had any test results at that point.

The test results came back positive for malaria and the child was started on chloroquine therapy. However, I still think based on the clinical picture, it would have been inappropriate to come to a provisional diagnosis of malaria, as there was no jaundice, the rapid course of the disease and mild grade of the fever, though certainly it was in the differential.

Interestingly, jaundice and hepatomegaly is associated with increased risk of acute renal failure in children suffering from malaria (1) but not an increase in the risk of cerebral malaria. However, in this case there was clinical finding of any abnormal renal function and the test results were within normal limits. There were also no features of CNS involvement (no headache, vomiting, visual disturbance, irritability or sleepiness), CSF examination was within normal limits.

1.  Nacher M, Treeprasertsuk S, Singhasivanon P, Silachamroon U, Vannaphan S, Gay F, Looareesuwan S, & Wilairatana P (2001). Association of hepatomegaly and jaundice with acute renal failure but not with cerebral malaria in severe falciparum malaria in Thailand. The American journal of tropical medicine and hygiene, 65 (6), 828-33 PMID: 11791981

Preventing Shingles

Shingles, also known as Herpes Zoster, usually occurs in elderly adults. It is characterized by painful eruption of vesicular lesions that follow a dermatomal distribution. The thoracic and lumbar roots are most commonly affected.

Pain precedes the appearance of the lesions and is severe and debilitating. The incidence and severity of herpes zoster increases with increasing age due to age related decline in immunity. Post herpetic neuralgia is a common complication of herpes zoster in the elderly. Facial nerve paralysis, herpes zoster ophthalmicus and bacterial superinfection are among other complications. Antiviral therapy with Acyclovir reduces the duration of the illness. A live attenuated Varicella Zoster Virus vaccine is also available to prevent herpes zoster.

Herpes zoster in the neck. Image from wikipedia.

In a recent study published in JAMA, Hung Fu Tseng et al. examined the effect of a Oka/Merck strain of varicella zoster virus based vaccine in reducing the incidence of herpes zoster. The study was a retrospective cohort study conducted among members of Kaiser Permanente, Southern California. The study included 75761 vaccinated subjects in 60 years or more age group. 227283 unvaccinated subjects in 60 years of more age group were included as controls. The controls were randomly selected and age matched. Immunocompromised individuals were excluded from the study as the vaccine is contraindicated in them. Exclusion of immunocompromised subjects also removes its confounding effect as it is a risk factor for herpes zoster. The main outcome of interest was incidence of herpes zoster. Bias was accessed by measuring the rate ratios of 13 different acute conditions which are not protected by the vaccine. If the rate ratios of these conditions are not grouped around 1, it would indicate that the vaccinated and the unvaccinated groups differ from each other and unmeasured confounders are at play. The rate ratio of herpes zoster was much greater in magnitude than the other conditions indicating that the outcome was not due to any bias.

In univariate analysis, the incidence of herpes zoster in vaccinated individuals was 6.4 (95% CI, 5.9-6.8) per 1000 person-years and among unvaccinated individuals, it was 13.0 (95% CI, 12.6-13.3) per 1000 person-years. The risk of herpes zoster among unvaccinated individuals varied with age, sex, race and lung disease. The difference in incidence of herpes zoster persisted upon adjustment for sex, race, chronic diseases and health care utilization. The fully adjusted analysis gave a hazard ratio of 0.45 (95% CI, 0.42-0.48). When a more strict criteria for immunocompetency was used, the adjusted hazard ratio was 0.46 (95%CI, 0.43-0.49). The vaccine also reduced the risk of herpes zoster ophthalmicus and hospitalization due to herpes zoster. Overall reduction in incidence of herpes zoster was 55%.

The limitations of the study are potentially unmeasured confounders and external validity.

Reference:

Tseng HF, Smith N, Harpaz R, Bialek SR, Sy LS, & Jacobsen SJ (2011). Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA : the journal of the American Medical Association, 305 (2), 160-6 PMID: 21224457

A Christmas tree in the eye

Medicine never ceases to amaze.  I just read a case report published in the BMJ by Ebube E Obi and C Weir about a Christmas tree cataract. I have seen some cases of cataract but I have not seen a Christmas tree cataract. May be sometime in future I will.

They report a case of a 73 year old woman who presented with a Christmas tree cataract of the left eye. The Christmas tree cataract was highly reflective, iridescent and polychromatic. They look like little needles in the eye going in all directions and assume the shape of a Christmas tree. The needles change color when the angle of the incident light is changed. The woman was referred to them for cataract surgery.

A Christmas tree cataract. From BMJ. 

Any opacity in the lens of the eye is called a cataract. Senile cataract is the commonest type though there are many other types. Usually it is accompanied by progressive impairment of vision but in Christmas tree cataract the vision may be 6/6 which is normal. In a Christmas tree cataract, the adjacent areas of the lens remain clear.

GA Shun-Shin et al. had examined the morphological and chemical composition of Christmas tree cataracts. They had examined four Christmas tree cataracts that were extracted and eight Christmas tree cataracts from donor eyes by scanning and transmission electron microscopy. Chemical composition was analyzed by energy dispersive x-ray microanalysis and Raman microspectroscopy.

Electron microscopy showed that Christmas tree cataracts were made up of rectilinear crystal like structures traversing the eye in all directions. The crystalline structures consisted of varying number of plate like elements stacked up together having a periodicity of about 5 nm. It has been suggested that the origin of these structures lie in the reticular meshwork. With increasing age there is degradation of the peptides and amino acids within the lens by endopeptidases. There is an increase in calcium ions and this local increase in calcium ions stimulates the endopeptidases resulting in protein breakdown. The breakdown products are subsequently deposited in the lumen of the reticular meshwork forming the Christmas tree cataract. Radiographic microanalysis showed the presence of sulfur in the crystals of the Christmas tree cataract. Raman microspectroanalysis showed increased CS-SC and S-S vibrations. The crystals are thus taken to be made of cystine (an amino acid). Accumulation of cystine beyond the point of crystallization causes the formation of needles that gives the fascinating appearance of the Christmas tree in the eye.

Reference:

Obi, E., & Weir, C. (2010). A Christmas tree cataract BMJ, 341 (dec08 3) DOI: 10.1136/bmj.c6644


Shun-Shin GA, Vrensen GF, Brown NP, Willekens B, Smeets MH, & Bron AJ (1993). Morphologic characteristics and chemical composition of Christmas tree cataract. Investigative ophthalmology & visual science, 34 (13), 3489-96 PMID: 8258504

How did Mozart die? In 140 ways!

I was going through an article published in the BMJ by Karhausen LR where he describes the different hypotheses put forward to explain the death of Mozart. Karhausen has listed 140 causes proposed to explain the death of Mozart even though he died only once.

Mozart. From BMJ.

In medicine a hypothesis is made by observing the facts, that is, case history and the clinical examination. The hypothesis is then tested by diagnostic tests. If the test results support the hypothesis, it is accepted. If not, it is rejected. Usually there are several competing hypotheses to explain a set of symptoms, termed as differential diagnosis. The final diagnosis is the one which is most favored by the evidence. On the other hand, in historical medicine usually there is no way to test a hypothesis. Surely we can say about the probability of a particular diagnosis but that’s pretty much all that can be said. Hence there arise many competing hypotheses, all vying for the position of final diagnosis.

Karhausen argues that in case of Mozart, the data has been manipulated to fit the hypothesis.

Most of the 27 psychiatric disorders attributed to Mozart result from disregarding or misquoting the criteria that demarcate normal from abnormal behaviour. Some authors upgrade daily worries into paranoid ideas or anxiety neuroses; blues or genuine worries into depression; elation into hypomania; linguistic games into jargonophasia; wit into immature or manic behaviour or into a childish, psychotic other self; the dissonant harmonies of the Haydn quartets into Tourette’s syndrome; and, at the end of his life, a small shuddering into a convulsion.

Much can be said about psychiatric conditions and without any hard evidence it is dependent upon interpretation. Karhausen comments that the psychological assessment of Mozart says much more about the psychobiographers themselves than it does about Mozart.

There is also a thing about the perspective from which different investigators approach. A cardiologist thinks of a heart condition first when he sees a patient whereas a nephrologist thinks about the kidneys when he sees the same patient. A microfungi expert, Schoental suggested Mozart died from mycotoxin poisoning. The neurosurgeon, Drake forwarded subdural hematoma. The cardiologist, Brown, thought of endocarditis whereas Langegger, the psychiatrist, thought of a psychosomatic cause. There is also a theory about Mozart being murdered by the Jews, the Freemasons or the Jesuits.

As the number of competing hypotheses put forward increases, the diseases become more uncommon and rarer. The common diseases had already been proposed, all that remains are increasingly uncommon. The list of diseases proposed to explain the death of Mozart can be used to form a short treatise on medicine. I like posthemorrhagic anemia. So Mozart survived a massive loss of blood, but died from anemia?

Karhausen ends by noting –

It [psychological hypothesis of Mozart’s death] covers the hidden intent to pull an exceptional creator down from his pedestal through some obscure need to cut great artists down to size.

The whole list of causes of Mozart’s death is available here.

Reference:

Karhausen, L. (2010). Mozart's 140 causes of death and 27 mental disorders BMJ, 341 (dec10 1) DOI: 10.1136/bmj.c6789

An unusual cause of Dysphagia

Difficulty in swallowing is called dysphagia. The causes of dysphagia can be divided into pre-esophageal and esophageal causes. While evaluating a case of dysphagia, it is important to consider whether it occurs in young age or old age, and the onset and subsequent progression of dysphagia. A sudden onset usually indicates an inflammatory process or foreign body impaction while a more gradual onset points towards a benign or malignant growth. Intermittent episodes of dysphagia may indicate spasmodic episodes.

Dysphagia and its relation to food is also important. Dysphagia to liquids usually indicates a motor impairment while dysphagia to solids indicates an obstructive lesion. Progressive dysphagia to both solids and liquids indicates malignancy.

While examining a patient of dysphagia, it is important to perform a thorough examination of the oral cavity, the oropharynx, hypopharynx, larynx, esophagus and the neck. The thyroid gland should also be examined along with neurological examination.

A case report published in the Indian Journal of Pediatrics reports a case of dysphagia due to lingual thyroid along with hypothyroidism. Lingual thyroid is developmental anomaly in which the thyroid analage arising from the ventral pharynx between the first and second pharyngeal pouch fails to descend in its normal position. The thyroid tissue is seen between the circumvallate papillae and the epiglottis at the base of the tongue. This may be the only functioning thyroid tissue in the body in 70% cases. It can present either in the young age or in adults. Symptomatic lingual thyroid is more common in adults. It can present with dysphagia, dysphonia, bleeding, difficulty in breathing. It can also present with hyperthyroidism or hypothyroidism.

MRI is the investigation of choice. It can also be visualized by CT scan. Radionuclide scanning using radioactive iodine or 99m Tc pertechnetate is also done to locate the thyroid glandular tissue. Thyroid function tests should also be done to evaluate the thyroid function. The differential diagnosis of midline mass at the base of the tongue is teratoma, carcinoma and soft tissue sarcoma.

In symptomatic patients the lingual thyroid can be surgically removed. In patients who are unfit for surgery or unwilling to undergo surgery it can also be treated with radioactive abalation of the thyroid.

Links:

• Lingual Thyroid causing Dysphagia.