Assessment and initial management of acute undifferentiated fever in tropical and subtropical regionsBMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4766 (Published 29 November 2018) Cite this as: BMJ 2018;363:k4766
- Anurag Bhargava, professor; head; adjunct professor1 2 3,
- Ravikar Ralph, assistant professor4,
- Biswaroop Chatterjee, professor5,
- Emmanuel Bottieau, professor of tropical medicine6
- 1Department of Medicine, Yenepoya Medical College, Mangalore, Karnataka, India
- 2Center for Nutrition Studies, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
- 3Department of Medicine, McGill University, Montreal, Canada
- 4Department of Medicine, Christian Medical College, Vellore, Tamil Nadu, India
- 5Department of Microbiology, IQ City Medical College, Durgapur, West Bengal, India
- 6Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
- Correspondence to: A Bhargava
What you need to know
Malaria, arboviral infections (such as dengue), enteric fever, and bacterial zoonotic diseases (such as scrub typhus and leptospirosis) are common causes to consider in patients presenting with acute fever and no localising symptoms in tropical regions
A step-wise approach—with a careful interpretation of local disease patterns, possible exposures and risk factors, clinical features, and basic laboratory data—can help clinicians recognise specific diseases
Request testing for malaria and a full blood count in all patients with acute undifferentiated fever
Early presumptive antibiotic therapy may be started for suspected bacterial zoonoses if diagnostic confirmatory tests are awaited or not available, as these infections may progress rapidly into a life threatening illness with multi-system involvement
Treatment for enteric fever needs to account for increasing drug resistance, especially in South Asia
Acute undifferentiated febrile illnesses (AUFI) are characterised by fever of less than two weeks’ duration without organ-specific symptoms at the onset.1 These may begin with headache, chills, and myalgia. Later, specific organs may be involved. AUFIs can range from mild and self limiting disease to progressive, life threatening illness. A mortality rate of 12% has been reported in severely ill hospitalised patients in tropical regions.2
AUFIs are classified into malaria and non-malarial illnesses with the help of microscopy or rapid diagnostic tests for malaria.3 The overlap of epidemiological and clinical features often renders clinical diagnosis difficult. There is greater focus on non-malarial AUFIs with the decline of malaria in many regions of the world.4 They account for 20-50% of all fevers in children over 5 years of age and adults in Asia and Africa.5 Laboratory confirmation is difficult—in contrast to malaria and dengue, for which high accuracy rapid diagnostic tests are now available. Current guidelines do not comprehensively address undifferentiated infections, which can fuel indiscriminate use of antimalarials and antibiotics.67
In this clinical update, we present an approach to the diagnosis and initial management of common AUFIs in children older than 5 years and in adults in tropical regions, taking into consideration availability of limited resources in some settings.
Sources and selection criteria
We searched PubMed for studies published in English between January 1990 and August 2018 using the MeSH terms: “(epidemiology, diagnosis, therapy, guideline) and (fever, bacteremia, typhoid fever, scrub typhus, rickettsial infections, spirochetal infections, arbovirus infections, malaria, brucellosis, melioidosis).” We also searched the Cochrane Database for related systematic reviews. Key references identified in review articles and textbooks were hand searched.
What are the causes of non-malarial AUFI?
Studies from Asia and Africa report arboviral infections (17.5% of severe febrile illnesses), bacterial bloodstream infections (mainly enteric fever) (10.5%), and bacterial zoonoses such as leptospirosis and rickettsioses (4.0% each) as major causes of non-malarial AUFI.68910111213 Box 1 presents the mnemonic “MA-ESR” as an aid to recall the common AUFIs, and figure 1 gives an overview of how undifferentiated fever is classified. Enteric fever affects an estimated 11.9 million people annually in Asia and Africa.14 Globally, over one million cases each of leptospirosis and scrub typhus occur annually.1516
Mnemonic MA-ESR lists the five main disease groups that cause acute undifferentiated febrile illnesses
Malaria—Including all malaria due to Plasmodium falciparum, P vivax, P ovale, P malariae, P knowlesi
Arboviral infections—Such as dengue, chikungunya, Japanese encephalitis, Zika, yellow fever
Enteric fever—Due to Salmonella enterica serovar Typhi and Paratyphi A, B, C
Spirochaete infections—Such as leptospirosis and tick-borne or louse-borne relapsing fever
Rickettsial infections—Including scrub typhus, murine typhus, spotted fevers
Rarer infections include viral haemorrhagic fevers such as Ebola virus disease and Lassa fever seen in Africa, and Crimean-Congo haemorrhagic fever (CCHF) with a wider distribution. Outbreaks of CCHF (also sometimes referred to as Asian Ebola virus) have been documented in Pakistan and India in recent years with high mortality.17181920 Timely recognition of these illnesses is important as they cause high mortality and spread rapidly.
How is it diagnosed?
Follow a typical stepwise approach to synthesise information from history and epidemiology. A careful history and physical examination can provide vital clues. Clinicians in settings with limited access to testing may have rely solely on these to formulate a probable diagnosis and start treatment (see fig 2).
Consider local pathogens, what season it is (some infections are particularly prevalent around rainy season), and activities or specific events that might give clues to the cause. Ask out about the onset, nature and features of the illness
Locally prevalent pathogens
The infographic lists common infections to consider by region (also see appendix 1 on bmj.com).21 Within regions considered endemic, the epidemiology of AUFIs is continuing to evolve. Scrub typhus and leptospirosis, once considered rural diseases, now affect urban populations too. Urban parks, and flooding in slums have emerged as risk factors for these respectively.2223 Dengue, once considered an urban disease, is increasingly observed in rural and peri-urban areas in India.24 Melioidosis is an important cause of community-acquired sepsis in northern Thailand and northern Australia, and is now recognised to be endemic in many countries of the Indian subcontinent, East Asia, sub-Saharan Africa.825
Arboviral infections, scrub typhus, leptospirosis, and melioidosis peak during the rainy season, similar to malaria. In many tropical areas, malaria occurs round the year. Seasonal dynamics of enteric fever are variable, with peaks after rainfall seen in northern latitudes.26 Information on ongoing outbreaks or a cluster of cases in a family or neighbourhood are useful clues to guide diagnosis.
Consider asking about:
Insect or mosquito bites, which are involved in transmission of several infections (malaria, dengue, chikungunya, Zika, CCHF, scrub typhus, murine typhus, spotted fevers, relapsing fever).
Ingestion of contaminated food and water, implicated in enteric fever.
Contact with body fluids or products of animals or contaminated water and soil, through skin abrasions or conjunctiva, which is linked to leptospirosis.
Walking barefoot, working in paddy fields, and flooding in urban areas, which are risk factors for scrub typhus and leptospirosis. In rural areas, the risks of exposure to a contaminated environment, contact with animals, and exposure to multiple vectors can coexist, making it difficult to estimate the risk of any particular disease.
Onset, duration and pattern of fever and illness
The pattern of fever can be disrupted by fever medications such as paracetamol and ibuprofen but may sometimes be typical of a specific infection.
Malaria, arboviral infections, scrub typhus, and leptospirosis have an abrupt onset and can rapidly progress to complications in the first week. A peak in temperature every other day is seen in malaria due to Plasmodium vivax or P ovale.27
Enteric fever has a more insidious onset. Fever >39°C (102.20°F) for more than three days with abdominal pain and diarrhoea or constipation can suggest enteric fever.
Dengue has a self limiting course with fever for up to 7-12 days.
Fever in influenza classically lasts three days but may persist for up to eight days.28
Fever may be absent or low grade in Zika infection.
Tropical borrelioses cause relapsing fever lasting 3-5 days between afebrile periods of 4-10 days.
Patient related factors
Age, comorbidities, immunosuppression, and pregnancy can help narrow the differential diagnosis, and also affect outcomes. For example, patients with diabetes have a higher risk of melioidosis.825 Bloodstream infection due to non-typhoidal Salmonella, disseminated tuberculosis, and deep mycoses are more commonly observed in adults with HIV infection.29 Pregnancy related immunosuppression is associated with increased severity of infections, in particular with more severe falciparum malaria.
Assess severity of illness
Look for signs of severe disease (see box 3) which indicate the need for urgent referral and hospitalisation.
Red flag signs in patients with acute undifferentiated febrile illnesses indicating need for hospitalisation and urgent treatment
Prostration—Unable to stand, sit, or walk without support30
Temperature—Hyperpyrexia (temperature >41.5°C) or hypothermia (temperature <36°C) or rigors
Respiration—Shortness of breath, respiratory rate >22 breaths/minute, cyanosis, arterial oxygen saturation <92% on room air31
Circulation—Blood pressure <100 mm Hg systolic,31 cold clammy extremities, capillary refill >3 seconds
Neurological—Altered mental status (Glasgow coma scale <13), convulsions, positive meningeal signs (such as neck stiffness and Kernig’s sign)31
Abdominal pain—Severe or persistent vomiting32
Severe conjunctival or palmar pallor30
Jaundice on examination of sclera30
Petechial or purpuric rash
Bleeding—From nose, gums, or venepuncture sites; haematemesis, melaena30
Rule out localised infections
Figure 3 indicates examination features consistent with a possible localised infection. Evaluate patients with fever, especially severe infection, for both localised infections and AUFIs. Influenza may be confused with AUFIs as fever and myalgia can initially overshadow respiratory symptoms, which may be absent in older people.28 Complicated AUFIs may also evolve and mimic localised infections—such as falciparum malaria (encephalitis), scrub typhus (severe pneumonia), or icteric leptospirosis (hepatobiliary infections).
Look for diagnostic clues of AUFIs
Certain clues on examination, which we term rule-in signs, help narrow the differential diagnoses (see infographic and appendix 2 on bmj.com). Rule-in signs, if present singly or in combination, indicate a moderate to high likelihood of a particular AUFI—that is, they are good predictors of a particular disease. There is limited evidence, however, on the diagnostic value of these signs.
Scrub typhus has a characteristic skin lesion—an eschar (fig 4)—seen in 17-57% of patients as per recent reports from India,3334 and in 56-86% of patients in reports from elsewhere in Asia.333435 Examine the neck, chest, axilla, abdomen, and groin for such lesions not associated with pain, pruritus, or oedema. A similar lesion in a patient with a milder illness in Africa is suggestive of African tick-bite fever, seen often in travellers returning from game parks. The lack of pain and oedema in eschars of rickettsial origin distinguish them from those of rarer causes such as tularaemia, anthrax, or East African trypanosomiasis.
Conjunctival suffusion (red eyes and oedema without exudate) and haemorrhage, jaundice, and marked muscle tenderness suggest leptospirosis (fig 5).36 A non-purulent conjunctivitis is also frequently seen in Zika virus infection, but not in other arboviral infections.
Rash and/or polyarthritis are suggestive of arboviral infections such as dengue, Zika or chikungunya. In Zika virus infection, a maculopapular rash appears typically on the first day with a cephalocaudal distribution and is intensely pruritic (worse in sleep). In contrast, the rash in dengue appears first on the trunk around five days after onset of fever.37
Symmetric arthritis of small joints with oedema is typical of chikungunya.37
Conversely, rule-out signs exclude a particular disease. For example, the presence of rash or lymphadenopathy renders malaria highly unlikely.38 Likewise, generalised lymphadenopathy is uncommon in enteric fever.3940 Jaundice with high fever makes a diagnosis of viral hepatitis less likely and instead suggests leptospirosis or other AUFIs with hepatic involvement.
What are the first investigations?
In endemic areas, request a complete blood count, urine analysis, and smear microscopy and/or rapid diagnostic test (RDT) for malaria in all patients with fever. Urine examination may reveal urinary tract infection, especially in women and older people as they may not present with localised symptoms. Biochemical tests (such as liver and renal function tests) and imaging (x ray and ultrasound) are useful in patients with localised symptoms and in patients with severe illness to detect complications. Table 1 describes the diagnostic value of findings on initial investigations.
Based on the suspected diagnosis, confirmatory tests for specific infections are requested (table 2). Spirochetal and rickettsial infections are confirmed by demonstration of either a IgM seroconversion (appearance of IgM in specimens about 10 days apart), or a fourfold elevation of IgG titre in a pair of specimens at least two weeks apart. This precludes their use in the immediate clinical decision making. Further, these tests have limitations in availability and sensitivity. The sensitivity of blood culture and PCR is influenced by duration of illness (highest in the first week), specimen type (highest with eschar in the case of scrub typhus), and by previous antibiotic treatment.
The specificity of serological tests is affected by cross-reactions among pathogens, and by persistence of IgM antibodies after infections. In practice therefore, diagnostic certainty eludes the physician dealing with a non-malarial AUFI, and the demonstration of IgM antibody in a single acute-phase specimen contributes, at best, to a “probable diagnosis” of leptospirosis and scrub typhus.
What are the possible complications?
Malaria, scrub typhus and leptospirosis can progress rapidly to multi-organ dysfunction within the first week. Severe scrub typhus and leptospirosis can present as bilateral pneumonia or pulmonary haemorrhage respectively, and evolve to acute respiratory distress syndrome.333471 Scrub typhus is an important cause of fever in pregnant women in Asia,7273 and has been associated with high rates of miscarriage (17%) and poor neonatal outcomes (42%).74
Dengue usually resolves within a week. Complications such as shock or bleeding characteristically occur 3-5 days after the onset of fever. Enteric fever typically has a subacute onset with complications such as encephalopathy, intestinal perforation, and bleeding only in the second or third week of illness.
How is it managed?
Clinically stable patients
Patients who are clinically stable with no red-flag features can be managed in the community. Treat patients with a confirmed diagnosis of malaria or dengue as per national guidelines or your local formulary.7879
For suspected bacterial AUFIs with characteristic clinical features it is prudent to start early presumptive antibacterial therapy if diagnostic confirmatory testing is awaited or not available. Infections such as rickettsioses and leptospirosis are rapidly progressive, and delay in treatment can increase severity and mortality.808182
Choose an appropriate antibiotic based on local disease and resistance patterns. In regions which are co-endemic for rickettsial infections and leptospirosis, especially in South-East Asia, doxycycline is an appropriate choice.83 Oral azithromycin is effective for uncomplicated enteric fever, scrub typhus, leptospirosis, and relapsing fever, and is another possible choice in regions co-endemic for these infections.84 Oral doxycycline is not advised in pregnancy, and azithromycin is an alternative.85
Severely ill patients
These patients must be immediately referred to a hospital and managed as inpatients. Empirical therapy with a combination of parenteral third generation cephalosporin (ceftriaxone) along with doxycycline or azithromycin is appropriate while diagnostic confirmation is awaited.8687 Ceftriaxone provides coverage for enteric fever, and leptospirosis; while doxycycline provides coverage for rickettsial infections. This combination is also appropriate for AUFIs complicated by pneumonia or acute respiratory distress syndrome, encephalopathy, and liver involvement87 and does not require dose modification in renal failure7988 and multi-organ failure. Finally, this combination may also be administered to patients suspected of, or diagnosed with, severe malaria, in addition to intravenous artesunate. Doxycycline would serve as a companion antimalarial drug to artesunate, and ceftriaxone and would address concomitant bacterial sepsis frequently seen in such patients.89
It is important to be aware of local resistance patterns. For example, extensively resistant typhoid fever has been documented in Pakistan since 2016, requiring the use of carbapenems or azithromycin.84 Additionally, local disease patterns guide choice of treatment. For example, in patients with AUFI followed by a severe pneumonia, if there is an influenza epidemic, it would be prudent to add oseltamivir pending confirmation of influenza by antigen test or RT-PCR, if available.90 In regions where melioidosis is common ceftazidime or meropenem may be an appropriate initial choice.
The response of fever to antibiotics can vary: rickettsial infections usually respond within 48 hours, while it may take up to a week in enteric fever, and longer in conditions such as melioidosis. The results of blood culture or serological tests may confirm the diagnosis and guide further therapy. Even if the fever responds to empirical therapy, a repeat specimen may be tested at follow-up a few weeks later to demonstrate IgM seroconversion or a fourfold rise in titre (see table 2) to confirm the probable diagnosis.
Review the diagnosis if fever persists after appropriate antibiotic therapy for other infectious causes of persistent fever.91 Clinical features of other causes of acute undifferentiated fever are mentioned in appendix 3.
Education into practice
From your practice records, identify the five most common causes of acute undifferentiated fever you have seen in your practice in the past six months?
How would you investigate a person presenting with acute undifferentiated fever?
What signs would prompt you to refer a patient with fever for hospitalisation?
How patients were involved in the creation of this article
No patients were involved in the creation of this article.
We thank Dr Anand Zachariah for his comments on the manuscript, Dr Prashant Upadhyaya for designing the infographics, and Dr Madhavi Bhargava, Dr Vineeth Nair, and Dr Sajjad Munaf for their help on preparing the manuscript for submission.
Contributors: AB formulated the approach and wrote the initial draft. All authors searched the literature, framed the content of the manuscript, made critical revisions, and approved the final version. RR and BC contributed equally.
Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.
Patient consent: Obtained.