Relative bradycardia and constipation in typhoid fever

Two of the buzzwords in typhoid that are oft-mentioned in clinical setting as well as in many literature are 1) relative bradycardia and 2) constipation.


Relative bradycardia (Faget sign):

But what exactly is relative bradycardia?

Cunha (2000) commented that this term has been vaguely described in a variety of literature and by many healthcare professionals leading to confusion.

Physiologically, for every one degree increase in Fahrenheit (read: Fahrenheit), heart rate increases by 10 beats/min.  Therefore, as 1 degree celcius equals to 9/5 (or 1.8 degrees) Fahrenheit, therefore the increase of every one degree celcius should be resulting in 18 beats/min. In some internet sources, this is allegedly known as the Leibermeister's rule.

In his editorial, Cunha (2000) also commented that relative bradycardia should only be applied to patients with temperature in excess of 102 F (or approx 39C).

The following criteria for relative bradycardia mentioned in the article:
1) Patient's age>13 years old
2) Temperature >102 deg Fahrenheit or 39 celcius
3) pulse must be taken simultaneously with the temperature elevation

Exclude patients with heart diseases such as AV nodal block, bradyarrhythmias, or patients on beta-blocker.

NOTE: Only Beta-blocker can interfere with the pulse-temperature relationship (meaning resulting in relative bradycardia) but not ACE inhibitors (A), calcium channel blockers (C) or digoxins (D) (which means: among the A-B-C-D, A, C and D does not cause relative bradycardia, only 'B' causes bradycarida) (Cunha, 2000).

But one thing for sure: FEVER + RELATIVE BRADCARDIA does not equal to typhoid as so often I have heard (even then, the term relative bradycardia has been misused so many times) as there are many other causes of relative bradycardia.

Causes of relative bradycardia include:

Infective causes

1. Typhoid fever
2. Dengue fever
3. Malaria
4. Leptospirosis
5. Typhus
6. Legionella
7. Psittacosis  
8. Q fever
9. Yellow fever
10. Babesiosis
11. Rocky Mountain spotted fever
12. Viral hemorrhagic fevers

Non-infective causes

1. Beta-blockers
2. CNS lesions (tumors, bleeds)
3. Lymphomas 
4. Drug fever
5. Fictitious fever

Constipation:
Constipation is another buzzword often mentioned in literature on typhoid.
WHO website mentions that constipation as a symptom of typhoid is more common than diarrhoeain adults and older children.

But in a response in BMJ titled "Constipation in Typhoid fever", it is commented that "there appears to be little recent evidence" that typhoid more often causes constipation than diarrhea. In that short comment, the author cited a number of small retrospective studies (and I quote):

Dimitrov et al (2007)
A retrospective analysis in Kuwait of 135 blood culture positive for S. typhi (101 cases, 74.8%) or S. paratyphi A (34 cases, 25.2%) over 4 years:

• diarrhoea occurred in 52.6% of cases vs
• constipation in only 3.7% of case 

Khan et al (1999) 
102 patients positive for S. typhi in Durban, South Africa:

• 16 (28.6%) of female patients and 10 (21.7%) of males patients had diarrhea
• Only 1 female had constipation

Deshmukh et al (1994)
Retrospective study

• Diarrhoea occured in 8 out of 28 Indian children (28.6%) diagnosed with a positive blood culture, Widal test or electrophoresis for S. typhi antigen. 
• No mention of constipation at all. 

Chowta et al (2005)
44 adult patients with typhoid fever hospitalized patients in an Indian Teaching Hospital in Manipal (1999 - 2001):

• 20.4% were reported to have diarrhoea
• only 9.09% constipation

Based on these studies, a large, systematic review of the incidence of constipation in typhoid fever is called for but in my anecdotal experience, I tend to agree with the above comment. I think constipation as a symptom of typhoid fever has really been over-estimated than it really is. I think it is another one of those stuffs which are good to test students in exam but in actual cases, they are not as common as mentioned in textbooks.

Update: 
Nobody knows for sure why constipation can occur in typhoid fever but Medscape emedicine.com explains that in typhoid fever:

"Monocytic infiltration inflames Peyer patches and narrows the bowel lumen, causing constipation that lasts the duration of the illness."(Brusch et al. Typhoid Fever. In: Medscape. Available at URL: http://emedicine.medscape.com/article/231135-clinical Accessed 21 September 2015)

Reference:

1. Cunha BA. The diagnostic significance of relative bradycardia in infectious disease. Clin Microbiol Infect 2000;6(12):633-4.

Dengue: The New WHO 2010 Severity Classification

WHO, in its recent dengue guidelines 2009, has alluded to the fact that its existing classification into dengue fever and dengue hemorrhagic fever (further divided into 4 grades) have a number of limitations due to the rigidity of its criteria.  Download also the Malaysian guidelines on dengue management.

For example,  in a number of cases, patients can present with dengue and shock but without fulfilling all the 4 criteria for DHF These patients would have been classified as dengue fever if the WHO criteria were strictly applied.

The requirement of 20% increase in HCT as one of the evidence of plasma leakage is difficult to fulfill due to several issues:

• Baseline hematocrit may not be easily available unless blood sampling for full blood count has been recently obtained in the same hospital or healthcare center where the patient presents himself to.
• Early fluid administration in a health clinic may have changed the hematocrit reading prior to referral to hospital.
• Bleeding itself will lower the HCT level

(* Previously, the following must ALL be present in order to classify the patients as having dengue hemorrhagic fever:

• Fever, or history of acute fever, lasting 2–7 days, occasionally biphasic.
• Haemorrhagic tendencies, evidenced by at least one of the following :

1. a positive tourniquet test
2. petechiae, ecchymoses or purpura
3. bleeding from the mucosa, gastrointestinal tract, injection sites or other locations
4. haematemesis or melaena.

• Thrombocytopenia (100,000 cells per mm3 or less).
• Evidence of plasma leakage due to increased vascular permeability, manifested by at least one of the following:

1. a rise in the HCT equal to or greater than 20% above average for age, sex and population
2. a drop in the HCT following volume-replacement treatment equal to or greater than 20% or baseline
3. signs of plasma leakage such as pleural effusion, ascites and hypoproteinaemia.)

As such, since 2009-2010, WHO and Malaysia has adopted a new classification that is more pragmatic. The whole idea is to capture early the group of patients that may potentially deteriorate due to the following pathogenetic processes:

Plasma leakage
Hemorrhage
Organ impairment

Under this classification, the patients would be classified into either

• Dengue fever (either probable or laboratory-confirmed)
• Dengue fever WITH warning signs
• Severe dengue (under which may have manifestations of severe plasma leakage, severe hemorrhage, severe organ impairment

For patients to be classified as dengue fever (probable), the pre-criteria is that any patients living in or travelling ENDEMIC AREA for dengue (including Malaysia) AND with FEVER and with 2 out of the following criteria:

• Nausea, vomiting
• Rash
• Aches and pains 
• Tourniquet test positive 
• Leukopenia 
• Any warning sign

These can be remembered with the following mnemonic:

AEEGYPTI (AEGYPTI)

A = Area endemic
E = Emesis
E = Exanthem (rash)
G = groan and ache
Y = yes to warning signs
P = Positive tourniquet test
T = total white cell low
I = increased temperature

Patients with dengue with warning signs need to be admitted.  These warning signs are:

Abdominal pain or tenderness 

Persistent vomiting

Clinical fluid accumulation 

Mucosal bleed

Lethargy, restlessness 

Liver enlargment >2 cm 

Laboratory: increase in HCT concurrent with rapid decrease in platelet count
The warning signs can be remembered by:
FLLLAVI (“Flavivirus”)

F = fluid accumulation
LLL = Liver, Lab, Lethargy
A = Abd pain
V = vomiting
I = “insignificant” bleed (“insignificant” does not mean “not important” but minor)

Other pointers in the diagnosis and management of dengue and severe dengue fever that should be kept in mind:

1. The earliest abnormality in the full blood count is a progressive decrease in total white cell count; not thrombocytopenia or increased hematocrit.

2. A relative bradycardia may be noted despite the fever, especially in the recovery phase. It is not always tachycardia in dengue.

3. Do not give acetylsalicylic acid (aspirin), ibuprofen or other non-steroidal anti-inflammatory agents (NSAIDs) as these drugs may aggravate the bleeding in dengue due to capillary fragility. Acetylsalicylic acid (aspirin) may be associated with Reye’s Syndrome.

4. Fresh whole blood or fresh red cells should be given whenever possible. This is because oxygen delivery at tissue level is optimal with high levels of 2,3 di-phosphoglycerate (2,3 DPG). Stored blood loses 2,3 DPG, low levels which may impede the oxygen-releasing capacity of hemoglobin.

5. If the haematocrit was low (<40% in children and adult females, <45% in adult males), this indicates bleeding and the need to cross- match and transfuse blood as soon as possible (see treatment for haemorrhagic complications).

The criteria in Surviving Sepsis Campaign Guideline for blood transfusion, i.e., hematocrit of <30% is not applicable to severe dengue. In fact, blood transfusion is life-saving and should be given as soon as severe bleeding is suspected or recognized. Do not wait for the haematocrit to drop too low before deciding on blood transfusion. This is because, in dengue, bleeding usually occurs AFTER a period of prolonged shock that is preceded by plasma leakage. During the plasma leakage the hematocrit IN FACT, increases to relatively high values before the onset of severe bleeding. As a result, when bleeding occurs in the later stage, hematocrit will then drop from this higher level; and therefore, it may not be as low as in the absence of plasma leakage.

6. A patient with normal SBP and normal mentation does not mean that he is not in shock. Patients in dengue shock often remain conscious and lucid. Look for narrowed pulse pressure despite normal SBP.

Once decompensation occurs, the BP may drop abruptly. Such prolonged hypotensive shock and hypoxia may in turn lead to multi-organ failure and an extremely difficult clinical course.

Differentiating chikungunya from dengue.
The key distinguishing feature for chikungunya is JOINT PAIN.

In fact, some clinicians came out with the aphorism “dengue + arthritis = chikungunya”!

The classical triad of clinical features for chikungunya infection are
•    fever,
•    arthralgia and
•    skin rash
(Ref: Robinson, M.C., 1955. An epidemic of virus disease in Southern Province, Tanganyika territory, in 1952-1953. Trans. R. Soc. Trop. Med. Hyg., 49 :28-32)
The arthralgia in chikungunya is usually symmetrical and involved more than one joint. The pain can be excruciating and involved fingers, wrist, elbows, toes, ankles and knees.

On the other hand, dengue presents with myalgia compared to chikungunya. The rash in chikungunya appears earlier (even in day 1 or 2 itself), as compared to dengue (around day 4). Furthermore, the rash in chikungunya starts with face and chest; those in dengue, the legs and trunks.