In this part of Dr. YK Amdekar's CME series he helps the readers to understand how to diagnose the root cause of fever with the help of case studies.

To begin, take the quiz below to test your knowledge.

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Cytokines mediate rise in body temperature and so the degree of fever depends on the amount of cytokines produced. A large amount of cytokines are produced in localised severe acute bacterial infection, wide-spread acute viral infection, and non-infective inflammation such as collagen vascular disorder or malignancy such as acute leukaemia. Hence these diseases present with high fever at the onset.

A sudden release of malarial parasites in blood also results in a high fever at onset. Low-grade fever at onset suggests low-grade infection or chronic infection. A moderate degree of fever at onset that increases to a higher degree over next 3-4 days suggest acute bacteraemia bacterial infection in which initial bacteraemia results in a moderate degree of fever that worsens when infection localises to intestines.

Generally, acute bacterial infection responds poorly to paracetamol with persistent sickness while fever in acute viral infection responds better to paracetamol with the child feeling better even with transient control of fever. Fever is often rhythmic in most infections except in case of typical malaria.

Fever in acute viral infections mostly settles by Day 3-4 without any specific therapy, fever in untreated acute bacterial infection worsens by D3-4 while there is no change in fever pattern by D3-4 in case of malaria or non-infective inflammatory diseases. Accompanying symptoms if any help early localisation of disease.

Following questions help in arriving at a provisional diagnosis in case of fever, even by D 2-3.

1. The degree of fever at onset (within first 24 hours)
2. Response to paracetamol (in terms of discomfort)
3. Behaviour during the interfebrile period (even with a small change in the reduction of fever)
4. The rhythm of fever (regular every 4-6 hours or irregular)
5. Progress by Day 3-4 (without specific antibiotic therapy)
6. Any accompanying symptoms (often cold, cough or other)

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Drawing diagnosis of Fever: Case Study

Case 1- No need for antibiotic

Two-year-old child presented with fever for a day. Fever was high at the onset, it responds fairly to paracetamol, the child feels better during the interfebrile period, fever is rhythmic coming up every 4-6 hours. Physical examination did not reveal any abnormality. High fever at the onset – four possibilities – acute bacterial infection at the site of entry (tonsillitis, bacillary dysentery, UTI), acute viral infection, non-infective inflammatory disease (collagen vascular disease, malignancy), malaria.

Fair response to paracetamol and better during interfebrile period rule out acute bacterial infection. Rhythmic fever is unlikely to be malaria. So at this juncture, fever is likely to be due to either viral infection or non-infective causes. One has to wait to see further progress.

On day 2, the child developed cold and cough. It suggests localisation to the respiratory tract. Physical examination revealed a fairly comfortable child, coryza, chest clear, no other abnormality. At this stage, you have already diagnosed it as an acute viral respiratory infection.

One can anticipate quick recovery over the next 2-3 days. Fever continued for another 2 days and then abated. However, cough continued for the next few days.

Thus, it is an acute viral respiratory infection. No need for an antibiotic. It is anticipated that a cough in acute viral infection may continue for a few more days and it does not call for change in diagnosis or treatment.

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Case 2-There is no single antibiotic that will treat effectively every bacterial infection

Two-year-old child presented with fever for a day.

• Fever was high at the onset, poor response to paracetamol with child remaining sick during the interfebrile period
• Fever would rise every 4 hours
• Physical examination revealed no abnormality
• Poor response to paracetamol with continued disturbed behaviour during the interfebrile period would have warned of oncoming acute bacterial infection even before localisation

Commonly acute bacterial infection may localise to the upper respiratory tract (tonsillitis, otitis media), lower respiratory tract (pneumonia), central nervous system (meningitis), the intestinal system (dysentery) or less commonly to other sites such as cervical lymph node or bone/joint. So, one has to observe the development of any localising symptoms.

On day 2, he developed abdominal pain and loose stools with blood and mucus. He was diagnosed with acute bacillary dysentery. He was treated with antibiotics and got better. Bacillary dysentery is caused by gram –ve bacteria and so antibiotic of choice could be cotrimoxozole or quinolones. Even Amoxicillin would work but may be reserved for gram +ve bacterial infections.

One has to wait for localisation before starting antibiotic even when one has suspected oncoming acute bacterial infection. It is because infection at different sites vary in choice of antibiotic and also its dosage.

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Case 3- Wait for probable diagnosis till infection localises; until diagnosis evolves, should not start any specific antibiotic therapy

Five-year-old child presented with fever for a day.

• Fever was low to moderate at onset, a fair response to paracetamol with normal interfebrile period and rhythmic pattern
• As this child’s fever was not high at onset, those four possibilities (acute bacterial infection at the site of entry, acute viral infection, non-infective inflammatory disease and malaria) are less likely though acute bacterial or viral infection of low virulence would still be possible. In such a case, we would have to wait and observe the further course
• Fever increased to a high degree on day 4 with poor response now to paracetamol and child looking sicker during the interfebrile period 
• So at this stage, it looks like an acute bacterial infection 
• The increasing trend of fever during first 3-4 days – moderate fever rising to a higher degree - suggests a bacteremic bacterial infection

During the bacteremic stage, the child develops a fever that increases once infection localises to some site. Three common localisation sites include lung (pneumonia), brain (meningitis) and intestine (typhoid). Though, lungs can be infected also directly through droplet infection reaching through airways. One has to observe localising symptoms. However, this child did not develop any significant localising symptoms such as breathlessness (pneumonia) or headache, vomiting (meningitis), though did complain of vague abdominal pain.

Physical examination showed mild abdominal distension and sick child on D 4. Typhoid fever was suspected and blood culture was sent for confirmation. In such a typical presentation, one may start antibiotic after sending out blood culture and not wait for results. This is because typhoid is a serious disease and early institution of antibiotic is ideal.

Blood culture proved the diagnosis of typhoid fever. Antibiotic of choice depends on local epidemiology but quinolone is the first drug of choice and it should be reserved if possible only for typhoid. Irrational use of quinolones has increased drug resistant bacterial infection.

Don’t use quinolones for routine infections. Provisional diagnosis may not be possible in the first 3 to 4 days in bacteremic bacterial infections. One has to wait for probable diagnosis till infection localises as may happen in case of meningitis or pneumonia or vague localisation in typhoid. Until diagnosis evolves, one should not start any specific antibiotic therapy.

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Case 4- Ruling out infective disease 

Five-year-old child presented with high fever at onset with fair response to paracetamol and better during the interfebrile period. This would rule out acute bacterial infection.

• Fever was rhythmic and so malaria is unlikely 
• That leaves only two possibilities - acute viral infection or non-infective inflammatory disease
• Physical examination did not reveal any abnormality
• So, at the end of the first day of fever, acute bacterial infection and malaria are nearly ruled out
• Fever continued for the next 4 days without any change
• Acute viral infection would have some accompanying symptoms and would have settled down by D 4
• Besides, the fever would rise every 12 hours and not every 4 to 6 hours as often happens in acute viral infection
• This means that longer afebrile period was not due to paracetamol effect but due to the natural course of the disease

Typically, the effect of paracetamol wanes off within 4 to 6 hours. At this stage, an acute viral infection is also ruled out and hence it is a non-infective inflammatory disease.

• Physical examination on D 4 did not reveal any abnormality
• One may not be able to guess further course that may evolve over another few days to sometimes even weeks
• But it is clear that it is not an infective disease and so investigations and therapy should not be addressed to infections
• Here again, one must wait and observe for the evolution of disease
• In such a case, one must watch for joint involvement, skin rash, mouth ulcers (all suggestive of collagen vascular disease), lymphadenopathy, pallor, purpura and bony tenderness (all suggestive of probable haematological malignancy)
• This child developed evanescent skin rash (rash appearing at the height of fever and disappearing when fever is controlled). It is a pointer to systemic inflammatory disease
• Two weeks later, he developed joint swelling and pain at which time it was diagnosed as the systemic onset of juvenile idiopathic arthritis
• Anti-inflammatory drugs such as Naproxan is the drug of choice and steroids are reserved only in selective cases, especially non-responders

Non-infective inflammatory disease can be suspected as early as 4th or 5th day though diagnosis is not known till disease evolves in a recognisable pattern. However, there is no need to start empirical antibiotic therapy just because fever continues longer.

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Case 5- Confirmation with peripheral blood smear is a must before starting anti-malarial therapy to avoid drug resistance

Five-year-old child presented with high fever at onset (four possibilities) with erratic rhythm irrespective of paracetamol (mostly malaria) and normal during the interfebrile period.

• Physical examination on D 2 did not reveal any abnormality
• Fever continued without any change or any other symptoms
• In a typical situation, malaria may be considered at the end of the first day of fever
• Diagnosis of malaria due to Plasmodium vivax infection was confirmed on peripheral blood smear
• Chloroquine is the drug of choice in uncomplicated vivax malaria
• Ideal dosage schedule should be adhered to
• Early in the course of malaria, there are no positive findings on clinical examination as pallor and splenomegaly come up later and are more prominent in recurrent malaria, however, history if well analysed can suspect malaria
• It is equally important to keep in mind that malaria can present with atypical findings

 

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Case 6- Low-grade fever at onset: it is important to confirm diagnosis of tuberculosis by bacteriological tests such as sputum culture 

Five-year-old child presented with low-grade fever at onset. Low-grade fever suggests infection with low virulence. Acute bacterial infection generally presents with high fever at the onset but subacute or chronic bacterial infection may present with low-grade fever as happens in tuberculosis.

 Acute viral infection may also present with low-grade fever because the host may be partially immune to such an infection either due to previous natural exposure to the same virus or prior vaccination against the same virus. Similarly, malaria may also present with low-grade fever if the host has had earlier exposure to malarial parasites. Systemic inflammatory diseases present with high fever at onset. So in this child, acute bacterial infection and non-infective inflammatory diseases are ruled out.

• Physical examination at this stage did not reveal any abnormality, so, one must wait before considering any antibiotic or laboratory investigations
• This is because one does not know which antibiotic and which test to order, moreover, this child is not seriously ill
• This child continued to run a low-grade fever for next one week without any other symptoms or signs
• At this stage, viral infection, as well as malaria, are mostly ruled out, so, one starts thinking about subacute or chronic bacterial infections such as tuberculosis
• Surely antibiotic is not necessary in this child as the acute bacterial infection has been ruled out, to begin with
• Further tests may have to be addressed to tuberculosis
• This child showed pneumonia on chest x-ray and tuberculosis was confirmed by subsequent tests
• Tuberculosis must be treated with four drugs for the first two months, followed by three drugs for the next 4 months, irrespective of type and site of disease 
• However, therapy may have to be prolonged beyond 6 months, as per the need
• Empirical anti-TB therapy has resulted in drug-resistant TB

It is important to confirm the diagnosis of tuberculosis by bacteriological tests such as sputum culture (in young children, gastric aspiration can replace sputum for culture as sputum is often swallowed by children and AFB can be picked up in gastric aspiration) or molecular tests such as GeneXpert. (It is available freely).

It is worth a note that there are enough facilities provided by the government for free diagnosis and treatment. Counselling a patient to ensure compliance of treatment is the major responsibility of a doctor.

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Case 7- Suspected acute bacterial infection in younger child demands ruling out UTI as early as possible

Two-year-old child presented with high fever at onset with poor response to paracetamol and continued to be sick during interfebrile period. This would suggest an acute bacterial infection. So one may carefully look for localisation- tonsillitis, otitis media, cervical lymphadenitis, UTI or bacillary dysentery.

• He did not develop any localisation over the next 24 hours
• Physical examination showed no abnormal signs

So, this rules out above mentioned conditions except for urinary tract infection that often has no specific localising symptoms and for which one should order routine urinalysis and culture, so as not to miss UTI.

• Routine urinalysis showed a large number of pus cells and urine culture-confirmed diagnosis of UTI

This child was treated with antibiotics covering gram –ve infections such as cotrimoxazole or norfloxacin and thereafter subjected to further tests to rule out congenital defects in the urinary system.

It is true that localisation of acute bacterial infection at the site of entry may get delayed beyond 2 to 3 days.

However, non-localised fever in a suspected acute bacterial infection in younger child demands ruling out UTI as early as possible. UTI is a serious disease in young children because it is likely to be due to congenital defects in the urinary system and so, if not treated properly would damage kidneys due to recurrent episodes of infections.

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Case 8- Does a headache justify considering it as meningitis?

Five-year-old child presented with high fever at onset accompanied by a headache. There was a fair response to paracetamol and he appeared well during interfebrile period. So at this stage, acute bacterial infection is unlikely.

Does a headache justify considering it as meningitis? Meningitis is a bacteremic infection and infection cannot reach meninges without going through the bloodstream. In such a case, localisation of infection occurs after 2 to 3 days. As a headache appeared at onset, it is not likely to be meningitis.

This child’s headache was due to high fever itself as a headache would go down as soon as fever was down. The child recovered within the next 3 days and was diagnosed with a viral infection. This child was treated without any specific therapy and was not subjected to any tests to rule out meningitis.

Headache and vomiting are non-specific symptoms that accompany any febrile disease. When such symptoms appear early in the course of the disease, a detailed history would reveal that symptoms disappear temporarily when fever is controlled by paracetamol.

In meningitis, headache and vomiting continue irrespective of temporary control of fever. Cause of fever can be suspected within first 2-3 days of fever and at times even at the end of the first day of fever. Until the cause of fever is known, all that one needs to be sure is to rule out any serious problem.

If the child’s behaviour is reasonably normal especially when fever is temporarily controlled with paracetamol, urine output is within normal limits and pulse/respiration are not disproportionately fast, one can be confident to rule out seriousness. Once a serious illness is ruled out, no antibiotic should be prescribed unless a bacterial infection is suspected and preferably confirmed.

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While medicine is a science of uncertainty, rational practice depends upon the art of probability. One can build confidence by repeated practice of following simple rules of historical analysis. It does not take time. And anyway, spending time for rational diagnosis is worth it.

You may read about the basics of Fever in the first part of CME here. 

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This article was originally published on January 25, 2019.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.