Pathology of Chikungunya Virus Infection: Emergence and Clinical Insights

Classic, Atypical & Severe Cases of CHIK in Adults

The classic symptoms after infection by CHIKV are abrupt febrile illness (temperature usually >38.9°C), maculopapular rash and articular pains responsible for a stooped walk. Other symptoms include myalgia, headache, edema of the extremities and gastrointestinal complaints.^[52,53] 'Chikungunya' means 'to walk bent over' in Tanzanian's language, and this is the canonical sign adopted by infected people in the acute phase (the incubation period ranges from 3 to 7 days, and as few as 5% of patients are asymptomatic) with a characteristic stooped walking position. Clinical presentations are often similar to those of Dengue fever, except for hemorrhagic or shock syndrome, which are only seen in CHIKV infection.^[54]

The diagnosis of CHIKV infection is based on either specific serology or by the detection of viral RNA (e.g., E1 gene) by reverse transcription PCR. Reverse transcription PCR is positive during the viremic phase (10⁹–10¹² viral RNA/ml of blood) lasting for 1 week after symptom onset, while the elevated levels of IgG (and surprisingly IgM) can last for months. CHIKV infection leads to protective adaptive immunity. IgM antibodies against CHIKV can be detected in the sera of infected patients during the acute phase of the infection. Antibody prevalence studies in many parts of Africa strongly suggest that anti-CHIKV (IgG), particularly neutralizing antibodies, may prevent virus reinfection and/or systemic multiplication in reinfected individuals.^[10,55] Interestingly, and in contrast to Dengue fever, the apparition of IgG anti-CHIKV was sometimes detected in the first week following infection, illustrating the rapid and robust adaptive immune response.^[56] As in the majority of infectious diseases, the host rapidly mobilizes a robust innate immune cellular and molecular response.^[57] Natural killer cells are strongly activated within the first few days postinfection and lead to a more sustainable CD4/CD8 response. Some, but not all, canonical cytokines and chemokines instigate the immune response and, surprisingly, the level of TNF-α is rather weak (almost undetectable) during the acute phase of CHIKV infection.^[57,58] Innate and adaptive immune responses are essential to ward off the infectious challenge, and hence, the acute signs usually resolve in less than 2 weeks (coinciding with the disappearance of CHIKV in the blood).^[57] However, incapacitating arthralgia may persist for weeks or months.

The 2005–2006 epidemic in La Réunion was the first time that severe cases and deaths due to CHIK fever were documented. This outbreak, which occurred in a tropical area with European health standards, has increased the chance of identifying previously unreported clinical presentations and of documenting clinical forms. A hospital-based surveillance system collected data on atypical CHIK cases,^[59] and patients with laboratory-confirmed CHIKV infection who developed other symptoms than fever and arthralgia were recorded as atypical cases. In addition, severe atypical cases were recorded when patients required maintenance of at least one vital function. A total of 610 adults presented with atypical cases of CHIK fever; the median age was 70 years (range: 15–95 years), and the sex ratio (M/F) was 0.8. Of these, 222 (36%) were severe cases, 84 (14%) were admitted to an intensive care unit and 65 of the severe cases (29%) died, accounting for an overall case–fatality rate of 10.7%.^[5] Overall, 546 cases had underlying medical conditions (226 cardiovascular, 147 neurological and 150 from respiratory disorders), 479 (78%) were on medication prior to hospitalization, 84 (14%) used NSAIDs and 88 (14%) were alcohol abusers.

In total, 110 patients were admitted with pre-renal acute renal failure and 41 (34%) presented with an exacerbation of a pre-existing renal disorder. Of these, 36 had chronic renal failure, two had a nephropathy and three had previously had a renal transplantation. Among 102 patients admitted with pneumonia, 17 had a history of chronic obstructive pulmonary disorder and three had asthma. A total of 131 patients presented with a glycemic impairment that revealed diabetes mellitus in 27 cases (20%). Although information on liver enzymes was only available for 64% of the cases, 73 patients had a greater than threefold increase of the liver enzymes. Of the 226 patients presenting with cardiovascular disease, 110 (49%) had an underlying cardiac condition and 137 (61%) had hypertension. Of the 84 patients with heart failure, 29 (35%) had underlying cardiomyopathy, ten (12%) coronary artery disease, six (7%) valvular disease and four (5%) a history of myocardial infarction. Of the 44 cases with arrhythmias, seven had known arrhythmias, six cardiopathy, two valvulopathy and one heart failure. Of the 35 cases with myocarditis or pericarditis, seven had an underlying cardiopathy, two arrhythmias and two had a history of myocardial infarction. Of the 25 cases diagnosed with angina pectoris, 15 (60%) had a history of coronary artery disease. Four patients presented with acute myocardial infarction, including two with a history of coronary artery disease.

In total, 147 patients had neurological disorders. Of these, 25 (17%) had underlying neurological conditions. Of the 69 cases with encephalitis, 12 (17%) had underlying neurological conditions, including five strokes and five epilepsies. Of the 15 cases with meningoencephalitis, one had a history of cysticercosis, one of hydrocephalus, one of myasthenia gravis and eight a diagnosis of hypertension. Eight out of 12 cases who developed seizures were previously healthy. Prior to the Indian Ocean epidemic, a single case of meningoencephalitis had been reported in a 5-year-old Cambodian boy in 1971.^[60]

Guillain–Barré syndromes that required respiratory support were recorded in adults for the first time during the La Réunion outbreak.^[61] Neurological symptoms started during the invasion phase prior to seroconversion. The presence of cerebrospinal fluid abnormalities and CHIK-specific IgM intrathecal synthesis were highly suggestive of CHIK-induced pathology in the nervous system. Tropism for brain tissue is a common occurrence in human viral disease that has been reported in some other arboviral infections and validated in several mouse models of CHIK neuroinfection.^[44,62,63] Ocular manifestations, such as defective vision linked with neuroretinitis, have also been reported.^[64]

A plethora of cutaneous manifestations were noted.^[65] Erythematous maculopapular or morbiliform eruption subsiding without any sequelae within 3–4 days was the most common cutaneous finding. Genital ulcers located predominantly over the scrotum and base of the penile shaft in men and labia majora in women were the second most common manifestation. Other manifestations included incapacitating edema of the hands and feet, hyperpigmented macules on the nose and cheeks, erythema nodosum, erythema multiforme, generalized urticarial eruptions and flare up of pre-existing lichen planus and psoriasis. Itching was reported in some cases. Peeling of the skin was observed in a few cases but remained uncommon in adults. Outcome was generally favorable, as the manifestations resolved rapidly in most cases, sometimes with scaling or persistence of dyschromic patches.^[66]

In La Réunion, the atypical cases aged 40–60 years were 2.5-times more likely to develop a severe disease than those aged less than 40 years. Those aged over 60 years were 1.6-times more likely to develop severe disease than those aged less than 40 years. In a recent study from India, age over 85 years was the only risk factor for mortality, although the possibility of coinfection by dengue virus (and other pathogens such as the respiratory syncytial or influenza viruses) may be contributing factors to be considered.^[67,68]