Normally, the colour yellow indicates brightness and sunshine, which implies optimistic and beautiful things. Yellow fever, however, doesn’t apply to this meaning because it’s a difficult disease that could cause dangerous and serious complications.

What is yellow fever?

Yellow fever is a viral disease that is transmitted through specific types of mosquitoes. It’s found in tropical and subtropical areas in Africa and South America. The name “yellow” comes from the jaundice that occurs in severe cases. The symptoms can vary from being simple and self-limited, to declining into severe complications. Although there is no specific antiviral therapy for this condition yet, there is an effective vaccine for it.¹

Up to 170,000 people across Africa and South America are infected with severe cases of yellow fever. On top of this, there are up to 60,000 deaths per year, with most of these deaths being in Africa.²

Yellow fever symptoms

At least half of those infected are asymptomatic, meaning they don’t present any symptoms and recover without any problems.² On the other hand, symptomatic patients may go through two phases of yellow fever, which is called a biphasic disease, consisting of the viremic and toxemic phases.²

Viremic phase

This phase occurs in mild and moderate cases, which account for 20-30% of infected patients.² This phase is characterised by flu-like symptoms, such as high fever (the mean duration is three days), headache, myalgia, nausea, and a lack of appetite. In most cases, these symptoms subside within 2-4 days.

Toxemic phase

About 15% of patients get to this phase. Usually, it comes after a stage of clinical improvement that lasts for about 24 hours.² This phase is characterised by the recurrence of the previous phase’s symptoms of high fever, chills and the worsening of myalgia, headaches, and the deterioration of particular body organs and systems. The symptoms in this phase might also include jaundice, bleeding, kidney dysfunction with oliguria, cardiovascular dysfunction, and neurological impairment with seizures. Half of these patients progress to death within 10-14 days, while the other half usually recover without any further complications.

Yellow fever complications

Kidney involvement

A study described lesions associated with disseminated mycoses (a fungal infection spread throughout the body) in kidneys found in autopsy reports of patients affected with the severe type of yellow fever.³ Furthermore, interstitial nephritis associated with tubular necrosis and interlobular thrombosis (blood clots) in kidney vessels was identified, in addition to haemorrhagic and ischemic necrosis of the adrenal gland. 

Another yellow fever patient autopsy report revealed that there was one irregular haemorrhagic area in the upper pole of one kidney and a 1.5 cm cyst on the anterior face of the other one.³ Moreover, the microscopic analysis revealed multiple interstitial nephritis foci, fibrosis and tubular necrosis.

Generally, kidney dysfunction in yellow fever appears within 5-7 days of the illness.³ They’re usually characterised by a reduction in urine volume in addition to the urinary loss of albumin (a blood protein). The main problem is that although there are biomarkers that can detect any abnormalities in the kidneys (like creatinine, levels of urea, etc.), there isn’t an available biomarker to accurately detect kidney dysfunction in a yellow fever condition.³ This is why patients with severe cases of yellow fever die from kidney failure within days before being able to be diagnosed with kidney dysfunction (about 20-50% of death cases involve liver and kidney failure).

Liver involvement

A study investigated the condition of the liver and how it can be severely infected in fatal cases of yellow fever.⁴ Examinations showed liver tissue damage due to cell death (apoptosis and necrosis). So as yellow fever worsens in severe cases, the liver begins to degenerate which leads to liver dysfunction and death.

Cardiovascular manifestations

There have been cardiac findings in some yellow fever patients, such as bradyarrhythmias and conduction abnormalities.⁵ Therefore, a study was conducted to perform a comprehensive cardiac evaluation of yellow fever patients and to assess the association between cardiac involvement and disease severity. Patients were divided into two groups according to the severity of yellow fever. Group 1 were patients with a mild and moderate form of yellow fever, and group 2 were patients with a severe form. The results were as follows:⁵ 

• Significant electrocardiogram (ECG) abnormalities: 52% were from group 1, and 77% were from group 2 
• Sinus bradycardia was observed in 24% (17) of total patients ): 23% were from group 1 and 25% were from group 2 
• Echocardiograms revealed left ventricular dysfunction in 4 (6%) patients from group 2 
• Other cardiac manifestations were also observed in some patients

In conclusion, cardiac involvement was observed in yellow fever patients, most commonly bradycardia and myocarditis.⁵

Neurological manifestations

 It is important to note that the yellow fever vaccination could lead to some neurological complications.⁶ A retrospective study was performed and included patients who had been vaccinated against yellow fever and 50 patients were suspected to have yellow fever neurological manifestations. Of these patients, 42 were in the final analysis which found:

• 24 cases that were classified as aseptic meningitis
• 8 patients who had encephalitis
• 2 patients were diagnosed with acute disseminated encephalomyelitis
• 2 patients experienced spastic quadriparesis
• Several cases of neurologic syndromes that are typically autoimmune or occur after infection, but are not traditionally associated with yellow fever vaccination 
• 2 patients who had died - one from aseptic meningitis and the other from encephalitis 

However, there is a necessary need for further studies.

There have been some reported cases of seizures in yellow fever patients who haven’t had any vaccination, and the underlying reason remains unclear.⁷

Haemorrhagic manifestations

A study was conducted to examine the severe complications of yellow fever.⁷ The coagulation workup revealed mild thrombocytopenia, a slight change in prothrombin time, and very low concentrations of coagulation factor V and fibrinogen. Haemorrhagic manifestations were observed in 65% of patients; most of them were gastric bleeding, followed by bleeding from the venipuncture site. Bleeding in these patients usually consisted of epistaxis or mild gingival bleeding, and intense bleeding developed within a few days. Unfortunately, severe gastrointestinal bleeding is one of the leading causes of death in severe yellow fever patients, along with necrohaemorrhagic pancreatitis, epileptic status, and severe metabolic acidosis.⁷

Respiratory manifestations

An autopsy was performed on two yellow fever patients who weren’t vaccinated and died as a result of dyspnea and rapidly progressive respiratory failure.⁸ Acute lung injury and pulmonary haemorrhage were diffused in both patients, and the lung damage began with capillaritis and, after that, bleeding from the microvasculature into the alveoli. Then, the expansion of the inflammation response into the epithelial-endothelial barrier triggered alveolar injury and increased haemorrhage. As a result, extensive septal necrosis occurred, highlighting pneumocyte injury, and diffuse alveolar haemorrhage (DAH). In the same affected areas, yellow fever antigens were highlighted in intra-alveolar macrophages.⁸

Ocular manifestations

A study was conducted to examine the ocular complications of yellow fever.⁹ Among the 64 patients in this study, 13 had retinopathy at the same time as yellow fever. The causes were mostly retinal nerve fibre layer infarcts, superficial haemorrhages, and greyish deep lesions possibly at the level of the outer retina or choroid. This means that 20% of patients are susceptible to retinopathy, mostly associated with the severe systemic stage of yellow fever.⁹

Other complications

Yellow fever can also cause other serious complications, such as sepsis and disseminated intravascular coagulation (DIC), and it’s estimated that approximately 39% of severe cases are fatal.^1,10

Management and prevention of yellow fever

Unfortunately, there isn’t a specific treatment for this condition, and that’s why prevention is extremely critical. As for vaccination, there is a safe and highly effective live-attenuated vaccine available to prevent yellow fever.¹ A single dose is sufficient for lifelong immunity and is effective within 30 days for 99% of patients.

However, the best prevention is accomplished by avoiding mosquito bites entirely.¹ It’s important to know that transmission is common in warmer months, and mosquitoes can bite through very thin clothing. Therefore, protection includes long sleeves, trousers, socks, and closed-toe shoes. You can also treat the clothes with repellents containing permethrin (not directly to the skin), lemon eucalyptus oil, or other EPA-registered insect repellents. Travellers should also sleep in air-conditioned spaces, or use mosquito nets or screens to prevent bites during sleep.¹

Summary

Yellow fever is a serious condition. Although more than half of the patients are asymptomatic or have simple common flu symptoms, a significant number of patients suffer from dangerous complications rapidly, which can be fatal. There isn’t a specific cure for yellow fever, but there is an effective vaccination. However, the best way to avoid this condition is by avoiding mosquito bites completely.