Bava Basra 155b ~ Delayed Puberty in Boys

In today's page of Talmud we read about the treatment for the delayed onset of puberty:

כי אתו לקמיה דרבי חייא אי כחוש אמר להו זילו אבריוהו ואי בריא אמר להו זילו אכחשוהו דהני סימנין זמנין דנתרי מחמת כחישותא וזמנין דנתרי מחמת בריותא

Whenever people came to Rabbi Hiyya [with a case of a man who had not developed pubic hair]  he would tell them, if [the man was] thin, ‘Let him gain weight’; and if they were overweight he would say ‘Go lose weight’; for these signs [of sexual maturity] are sometimes delayed as a result of emaciation and sometimes  as a result of obesity.   (Yevamot 97a)

Rabbi Hiyya probably lived in the second half of the second century, and the treatment he suggested is one of the earliest examples associating nutritional status and delayed puberty.  Elsewhere in the Talmud we find this statement attributed to Rava, who died around 350 CE. But whoever suggested it first, I have found nothing in the works of Hippocrates, Aristotle and Galen that address this issue, so this association does not appear to have been a widely held belief in antiquity that was simply being echoed in the Talmud. 

There has been some discussion of what appears to be the increasingly earlier onset of puberty in girls. In fact, menarche, (the age of a girl's first menstrual period) has been steadily decreasing by a consistent three years per century of record keeping. However, R. Hiyya was addressing not the early onset of puberty in girls, but its delayed appearance in boys.  He noted that this delay was sometimes related to extremes of nutritional status, and so in these cases, was amenable to intervention.

“R.Hiyya may have been the first first to report an association of obesity and delayed puberty in boys.”

R.Hiyya was on to something. He (or Rava) may in fact have been the first to report an association between obesity and delayed puberty in boys.  This association has been confirmed by several studies which found that obesity has different effects on puberty in boys and girls. In girls, obesity is associated with earlier puberty, while in boys it has the opposite effect, and delays sexual maturation. But it was not until 2010 this association was confirmed by a longitudinal population-based study. This reported that a "higher BMI z score trajectory" (i.e. obesity)  during early to middle childhood may be associated with later onset of puberty among boys. 

The finding that puberty may be delayed in boys who are underweight has also been confirmed. As far as I can tell, none of the researchers has credited Rava (who died around 350 CE.) or Rabbi Hiyya for being the first to notice these associations. But they were first, and firsts count for something in science.

Nedarim 41b ~ Fever

נדרים  מא, א–ב

אמר רבא האי אישתא אי לאו דפרוונקא דמלאכא דמותא מעלי כחיזרא לדיקלי חד לתלתין יומין

Rava said about a fever: "Were it not for the fact that it is an agent of the Angel of Death, it would be beneficial for a person as a prickly foliage is for palm trees, if it is experienced once every thirty days...(Nedarim 41a-b).

When I worked as an emergency physician I treated hundreds and hundreds of patients who came to the ER with a fever.  In fact, fever is the third most common reason in the US for which people visit the ER - accounting for over 5 million visits each year. At virtually every visit they'd be given a medicine to reduce their fever, as if by doing so we were achieving something medically important. But in this page of Talmud, we read that according to Rava, fever is actually beneficial to a person (at least when it does not kill...).  How does this claim made by Rava, a Babylonian sage who died around the year 352 CE, stand up to today's medical science? Remarkably well, it turns out. Here's why.

Fever 101

Here are some basic things to know about fever. First, it is usually defined as a core temperature in humans above 38.3 C, or 101 F.  Second, there are lots of reasons why people get a fever, of which bacterial and viral infections are the most common, but not the only causes.  Third, and this is really important, not all fevers mean the same thing in terms of their seriousness.  Fever in a baby less than a month old requires an urgent and extensive evaluation. The same fever in a healthy toddler does not.  Fever in a healthy teenager is not the same as fever in an elderly patient on chemotherapy.  Finally, fever is not caused by the infection, at least not in the way you might think. It is the body's response to that infection that produces a fever.  Here's how.

The Biochemical Pathway to Fever

When bacteria infect the body, their foreign structure is recognized by white cells in the blood called macrophages. These macrophages then release a prostaglandin E2, interleukin-1, interleukin-6, and tumor necrosis factor. These act on a region deep in the brain called the hypothalamus, which acts as a thermostat for the body. Under the influence of interleukin-1 the hypothalamus releases a hormone called cyclooxygenase 2 (COX-2) which resets the body's thermostat, causing the temperature of the body to rise by a few degrees.  

How a fever is caused by a bacterial infection. From Evans, Repasky and Fisher. Fever and the thermal regulation of immunity: the immune system feels the heat. Nature Reviews Immunology June 2015: 15: 337.

It's not just people who get fevers. Dogs and cats do too, as do mice (and all mammals), reptiles, and even goldfish. Why would so many animals respond to an infection by developing a fever?

The Benefits of Fever

The reason is simple. The immune system fights infections better when the body is hotter. The way it does this is now well-understood but very complicated; here are just the highlights. 

Under what immunologists call "thermal stress" (and the rest of us call "a fever,") neutrophils, the white cells that are needed to fight infection, are released in greater numbers from the bone marrow.  These neutrophils also do a better job of fighting bacteria at the site of the infection when the body is warmer.  Fever also improves the killing ability of another group of blood cells called natural killer cells, and it increases the ability of the macrophages to ingest and destroy the invading bacteria. In an excellent review of fever and the thermal regulation of immunity in Nature Reviews, the authors concluded that "[t]he picture that emerges is one in which febrile temperatures serve as a systemic alert system that broadly promotes immune surveillance during challenge by invading pathogens."  

So your body does a better job of fighting bacteria when it is hotter.  Why then, do doctors give medicines that reduce a fever?  Good question. The truth is, they really shouldn't.

Don't Reach for That Tylenol/Paracetomol/AcAmol 

If you are the parent of a child with a fever, you are likely to give your sick offspring a medicine that interferes with the immune system, like Tylenol if you are in the US, Paracetamol if you are in the UK or South Africa, or Acamol in Israel (though they are different words for the same medicine).  But if, as we have seen, the body does a better job of fighting infection when it is a few degrees hotter, might reducing the fever lead to a worse outcome for the child?

This question was recently examined by a group from McMaster University in Canada. They looked at the side effects of reducing a fever in those who are sick from a population level . What happens in a large group of people when some of them - infected with, say, influenza - take medicines to reduce their fever? The answer is that more of them transmit the virus and so more of them fall ill.  On a population level the effect is rather drastic:

Putting together our estimates of the treatment probability p and the individual transmission enhancement factor fi ...we conclude that the current practice of frequently treating fevers with antipyretic medication has the population-level effect of enhancing the transmission of influenza by at least 1% (95% CI: 0.04–3%)...This estimate does not take into account the known effect that the infectious period of influenza is also increased by antipyresis, nor does it take into account the potentially large effect of increasing the rate of contact among infectious and susceptible individuals because antipyresis makes infectious individuals feel better...To put our lower bound...into perspective, consider that approximately 41,400 ...deaths per year are attributed to seasonal influenza epidemics in the United States (and an order of magnitude more worldwide). Taken at face value, our results indicate, for example, that...at least 700 deaths per year ... could be prevented in the US alone by avoiding antipyretic medication for the treatment of influenza...

“In the absence of meaningful evidence for the beneficial effects of fever reduction, the commonplace reduction of fever in critically ill patients must be called into question.”

— Ryan and Levy. Clinical Review: Fever in intensive care patients. Critical Care 2003, 7:224.

The Canadian investigators concluded that "...the use of antipyretics can have subtle and potentially important negative effects at the population level. Any medical intervention that aims to relieve the symptoms of an infectious disease in an individual should also be evaluated in light of potentially harmful effects at the population level..." And it's not just populations that can suffer: individual patients are at risk too. In a 2011 paper looking at the treatment of fever in very ill patients with sepsis in the ICU,  a French team looked at the beneficial and detrimental effects of fever, and concluded that "...the widespread use of antipyretic methods in ICU patients is not supported by clinical data and fever control may be harmful, particularly when an infectious disease is progressing..."

From Lainey Y. et al. Clinical review: Fever in septic ICU patients - friend or foe? Critical Care 2011:15:222

The Death of Rav Assi - from Fever

So Rava's teaching in tomorrow's daf, Nedarim 41b appears to be spot on.  Fever is indeed beneficial for the body, though it is a sign that something bad is going on.  Elsewhere in the Talmud (Niddah 36b, which we will learn on Shabbat, May 1, 2027, הבא עלינו לטובה) we read that another Babylonian Amora, Rav Assi, died from a fever accompanied with chills - the classic description of sepsis (and a lot else besides, too). It is interesting to note that Rav Assi's attendants tried to reduce his fever.  Perhaps they were not aware of the tradition that Rava - who was born two generations later - would later teach.

R. Assi fell ill and they had to put him in hot [blankets] to relieve him from chills, and in cold [compresses] to relieve him from heat,[but] his soul departed to its eternal rest. (Niddah 36b.)

Fever may be beneficial, but the underlying infection of which it is a sign never is.  Which is why, in the next daf  (Nedarim 42), Rava's teaching was not accepted by Rav Nachman bar Yitzchak who retorted: לא היא ולא תירייקה:  "Give me neither fever, nor its antidote!"

Yevamot 97a ~ Rava on Delayed Puberty in Boys

THIS POST IS PART TWO OF TWO, ABOUT TODAY’S PAGE OF TALMUD.

On this page of Talmud we read of Rava's observation that delayed puberty may be related to body mass:

יבמות צז, א

כי אתו לקמיה דרבא אי כחוש אמר להו זילו אבריוהו ואי בריא אמר להו זילו אכחשוהו דהני סימנין זמנין דנתרי מחמת כחישותא וזמנין דנתרי מחמת בריותא

Whenever people came to Rava [with a case of a man who had not developed pubic hair]  he would tell them, if [the man was] thin, ‘Let him gain weight’; and if they were overweight he would say ‘Go lose weight’; for these signs [of sexual maturity] are sometimes delayed as a result of emaciation and sometimes  as a result of obesity.   (Yevamot 97a)

There has been some discussion of what appears to be the increasingly earlier onset of puberty in girls. In fact, menarche, (the age of a girl's first menstrual period) has been steadily decreasing by a consistent three years per century of record keeping. In an article in The New York Times published only a couple of weeks ago, the headline read “Puberty Starts Earlier Than It Used To. No One Knows Why.” It noted that “some girls are starting to develop breasts as early as age 6 or 7.”

However, Rava was addressing not the early onset of puberty in girls, but its delayed appearance in boys.  He noted that this delay was sometimes related to extremes of nutritional status, and so in these cases, was amenable to intervention.

“Rava may have been the first first to report an association of obesity and delayed puberty in boys.”

Rava was on to something. He may in fact have been the first to report an association between obesity and delayed puberty in boys.  This association has been confirmed by several studies which found that obesity has different effects on puberty in boys and girls. In girls, obesity is associated with earlier puberty, while in boys it has the opposite effect, and delays sexual maturation. But it was not until 2010 this association was confirmed by a longitudinal population-based study. This reported that a "higher BMI z score trajectory" (i.e. obesity)  during early to middle childhood may be associated with later onset of puberty among boys. 

Rava also claimed that puberty may be delayed in boys who are underweight, and this has also been confirmed. As far as I can tell, none of the researchers has credited Rava (who died around 350 CE.) for being the first to notice these associations. But Rava was first, and firsts count for something in science.

Rabbi Hiyya’s claim

The same passage is repeated in Bava Basra (155b) but in the name of Rabbi Hiyya.  Hiyya probably lived in the second half of the second century, and so predated Rava by a few decades.  The claim of primacy regarding the association with nutritional status and delayed puberty may therefore have to be extended back to R. Hiyya.  But so far I have found nothing in the works of Hippocrates, Aristotle and Galen that address this issue, so this association does not appear to have been a widely held belief in antiquity that was simply being echoed in the Talmud. As all good scientific papers end, further research is needed...

Niddah 36 ~ Fever

נדה לו, ב

חלש רב אסי עיילוה בחמימי אפקוה מקרירי עיילוה בקרירי אפקוה מחמימי נח נפשיה דרב אסי

Rav Assi became ill. When he had a fever his chills were relieved, and when he had chills his fever ended. Eventually, Rav Assi died.

We have previously discussed fevers in the Talmud, when we read the tractate Nedarim.

נדרים  מא, א–ב

אמר רבא האי אישתא אי לאו דפרוונקא דמלאכא דמותא מעלי כחיזרא לדיקלי חד לתלתין יומין

Rava said about a fever: "Were it not for the fact that it is an agent of the Angel of Death, it would be beneficial for a person as a prickly foliage is for palm trees, if it is experienced once every thirty days...(Nedarim 41a-b).

As an emergency physician I've treated hundreds and hundreds of patients who came to the ER with a fever.  In fact fever is the third most common reason in the US for which people visit the ER - accounting for over 5 million visits each year. At virtually every visit they'd be given a medicine to reduce their fever, as if by doing so we were achieving something medically important. But here we read that according to Rava, fever is actually beneficial to a person (at least when it does not kill you as it did poor Rav Assi).  Was Rava, a Babylonian sage who died around the year 352 CE, correct when he claimed that a fever might be good for you? He was, as it turns out. Here's why.

Fever 101

Here are some basic things to know about fever. First, it is usually defined as a core temperature in humans above 38.3 C, or 101 F.  Second, there are lots of reasons why people get a fever, of which bacterial and viral infections are the most common, but not the only causes.  Third, and this is really important, not all fevers mean the same thing in terms of their seriousness.  Fever in a baby less than a month old requires an urgent and extensive evaluation. The same fever in a healthy toddler does not.  Fever in a healthy teenager is not the same as fever in an elderly patient on chemotherapy.  Finally, fever is not caused by the infection, at least not in the way you might think. It is the body's response to that infection that produces a fever.  Here's how.

The Biochemical Pathway to Fever

When bacteria infect the body, their foreign structure is recognized by white cells in the blood called macrophages. These macrophages then release a prostaglandin E2, interleukin-1, interleukin-6, and tumor necrosis factor. These act on a region deep in the brain called the hypothalamus, which acts as a thermostat for the body. Under the influence of interleukin-1 the hypothalamus releases a hormone called cyclooxygenase 2 (COX-2) which resets the body's thermostat, causing the temperature of the body to rise by a few degrees.  

How a fever is caused by a bacterial infection. From Evans, Repasky and Fisher. Fever and the thermal regulation of immunity: the immune system feels the heat. Nature Reviews Immunology June 2015: 15: 337.

It's not just people who get fevers. Dogs and cats do too, as do mice (and all mammals), reptiles, and even goldfish. Why would so many animals respond to an infection by developing a fever?

The Benefits of Fever

The reason is simple. The immune system fights infections better when the body is hotter. The way it does this is now well-understood but very complicated; here are just the highlights. 

Under what immunologists call "thermal stress" (and the rest of us call "a fever",) neutrophils, the white cells that are needed to fight infection, are released in greater numbers from the bone marrow.  These neutrophils also do a better job of fighting bacteria at the site of the infection when the body is warmer.  Fever also improves the killing ability of another group of blood cells called natural killer cells, and it increases the ability of the macrophages to ingest and destroy the invading bacteria. As last month's excellent review of fever and the thermal regulation of immunity in Nature Reviews concluded, "[t]he picture that emerges is one in which febrile temperatures serve as a systemic alert system that broadly promotes immune surveillance during challenge by invading pathogens."  

So your body does a better job of fighting bacteria when it is hotter.  Why then, do doctors give medicines that reduce a fever?  Good question. The truth is, they really shouldn't.

Don't Reach for That Tylenol/Paracetomol/AcAmol 

If you are the parent of a child with a fever, you are likely to give your sick offspring a medicine that interferes with the immune system, like Tylenol if you are in the US, Paracetamol if you are in the UK or South Africa, or Acamol in Israel (though they are different words for the same medicine.)  But if, as we have seen, the body does a better job of fighting infection when it is a few degrees hotter, might reducing the fever lead to a worse outcome for the child?

This question was recently examined by a group from McMaster University in Canada. They looked at the side effects of reducing a fever in those who are sick from a population level . What happens in a large group of people when some of them - infected with, say, influenza - take medicines to reduce their fever? The answer is that more of them transmit the virus and so more of them fall ill.  On a population level the effect is rather drastic:

Putting together our estimates of the treatment probability p and the individual transmission enhancement factor fi ...we conclude that the current practice of frequently treating fevers with antipyretic medication has the population-level effect of enhancing the transmission of influenza by at least 1% (95% CI: 0.04–3%)...This estimate does not take into account the known effect that the infectious period of influenza is also increased by antipyresis, nor does it take into account the potentially large effect of increasing the rate of contact among infectious and susceptible individuals because antipyresis makes infectious individuals feel better...To put our lower bound...into perspective, consider that approximately 41,400 ...deaths per year are attributed to seasonal influenza epidemics in the United States (and an order of magnitude more worldwide). Taken at face value, our results indicate, for example, that...at least 700 deaths per year ... could be prevented in the US alone by avoiding antipyretic medication for the treatment of influenza...

“In the absence of meaningful evidence for the beneficial effects of fever reduction, the commonplace reduction of fever in critically ill patients must be called into question.”

— Ryan and Levy. Clinical Review: Fever in intensive care patients. Critical Care 2003, 7:224.

The Canadian investigators concluded that "...the use of antipyretics can have subtle and potentially important negative effects at the population level. Any medical intervention that aims to relieve the symptoms of an infectious disease in an individual should also be evaluated in light of potentially harmful effects at the population level..." And it's not just populations that can suffer; individual patients are at risk too. In a 2011 paper looking at the treatment of fever in very ill patients with sepsis in the ICU,  a French team looked at the beneficial and detrimental effects of fever, and concluded that "...the widespread use of antipyretic methods in ICU patients is not supported by clinical data and fever control may be harmful, particularly when an infectious disease is progressing..."

From Lainey Y. et al. Clinical review: Fever in septic ICU patients - friend or foe? Critical Care 2011:15:222

The Death of Rav Assi - from Fever

So Rava's teaching found on Nedarim 41b is scientifically accurate.  Fever is indeed beneficial for the body, though it is a sign that something bad is going on.  Which is what happened on today’s page of Talmud when another Babylonian Amora, Rav Assi, died from a fever accompanied with chills - the classic description of sepsis (and a lot else besides, too). It is interesting to note that according to the Soncino translation of today’s passage of Talmud, Rav Assi's attendants tried to reduce his fever.  Perhaps they not aware of the tradition that Rava - who was born two generations later - would later teach.

R. Assi fell ill and they had to put him in hot [blankets] to relieve him from chills, and in cold [compresses] to relieve him from heat,[but] his soul departed to its eternal rest.

Fever may be beneficial, but the underlying infection of which it is a sign never is.  Which is why Rava's teaching was not accepted by by Rav Nachman bar Yitzchak who retorted (Nedaraim 42,): לא היא ולא תירייקה:  "Give me neither fever, nor its antidote!" Rav Assi probably thought the same thing.

[Mostly a repost from here.]