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Clinical and laboratory predictors of Lassa fever outcome in a dedicated treatment facility in Nigeria: a retrospective, observational cohort study

https://doi.org/10.1016/S1473-3099(18)30121-XGet rights and content

Summary

Background

Lassa fever is a viral haemorrhagic disease endemic to west Africa. No large-scale studies exist from Nigeria, where the Lassa virus (LASV) is most diverse. LASV diversity, coupled with host genetic and environmental factors, might cause differences in disease pathophysiology. Small-scale studies in Nigeria suggest that acute kidney injury is an important clinical feature and might be a determinant of survival. We aimed to establish the demographic, clinical, and laboratory factors associated with mortality in Nigerian patients with Lassa fever, and hypothesised that LASV was the direct cause of intrinsic renal damage for a subset of the patients with Lassa fever.

Methods

We did a retrospective, observational cohort study of consecutive patients in Nigeria with Lassa fever, who tested positive for LASV with RT-PCR, and were treated in Irrua Specialist Teaching Hospital. We did univariate and multivariate statistical analyses, including logistic regression, of all demographic, clinical, and laboratory variables available at presentation to identify the factors associated with patient mortality.

Findings

Of 291 patients treated in Irrua Specialist Teaching Hospital between Jan 3, 2011, and Dec 11, 2015, 284 (98%) had known outcomes (died or survived) and seven (2%) were discharged against medical advice. Overall case-fatality rate was 24% (68 of 284 patients), with a 1·4 times increase in mortality risk for each 10 years of age (p=0·00017), reaching 39% (22 of 57) for patients older than 50 years. Of 284 patients, 81 (28%) had acute kidney injury and 104 (37%) had CNS manifestations and thus both were considered important complications of acute Lassa fever in Nigeria. Acute kidney injury was strongly associated with poor outcome (case-fatality rate of 60% [49 of 81 patients]; odds ratio [OR] 15, p<0·00001). Compared with patients without acute kidney injury, those with acute kidney injury had higher incidence of proteinuria (32 [82%] of 39 patients) and haematuria (29 [76%] of 38) and higher mean serum potassium (4·63 [SD 1·04] mmol/L) and lower blood urea nitrogen to creatinine ratio (8·6 for patients without clinical history of fluid loss), suggesting intrinsic renal damage. Normalisation of creatinine concentration was associated with recovery. Elevated serum creatinine (OR 1·3; p=0·046), aspartate aminotransferase (OR 1·5; p=0·075), and potassium (OR 3·6; p=0·0024) were independent predictors of death.

Interpretation

Our study presents detailed clinical and laboratory data for Nigerian patients with Lassa fever and provides strong evidence for intrinsic renal dysfunction in acute Lassa fever. Early recognition and treatment of acute kidney injury might significantly reduce mortality.

Funding

German Research Foundation, German Center for Infection Research, Howard Hughes Medical Institute, US National Institutes of Health, and World Bank.

Introduction

Lassa fever is a viral haemorrhagic disease, endemic to west Africa, where it imposes a substantial health burden.1 First described in 1969,2 Lassa fever's causative agent is the Lassa virus (LASV), a member of the Arenaviridae family and a biosafety level 4 pathogen. The main reservoir and primary source of infection is the multi-mammate mouse (Mastomys natalensis), but the virus also spreads between human beings via contact with body fluids of an infected person. An estimated 100 000–300 000 people are infected with LASV every year in west Africa, although the overall incidence is likely to be underestimated.3 Most individuals infected with LASV are never diagnosed with Lassa fever because of mild or asymptomatic presentation of the disease. Between 10% and 20% of patients treated in hospital with Lassa fever die, which can be much higher in outbreak settings or in individuals at increased risk.4 The only known treatment is the antiviral drug ribavirin, shown to be most effective in the first 6 days after onset of symptoms.5 No vaccine is available, although progress has been made with human monoclonal antibodies in preclinical animal models.6, 7

Despite the endemic nature and high mortality of Lassa fever, its underlying mechanisms of disease are not fully understood.8 Few large-scale clinical studies have been done and most are limited to Sierra Leone and Liberia despite the vast geographical reach of the virus (appendix). These studies show a wide spectrum of clinical severities, from asymptomatic infection to serious multiorgan dysfunction, haemorrhage, and neurological manifestations. Even among acute cases, observations range from minimal cell damage in the liver and kidneys to more extensive involvement of these organs.9, 10 Only one study11 of cases in Sierra Leone in the late 1970s has modelled Lassa fever outcome with the aim to assist physicians in making early prognoses on the basis of clinical features, and it remains the most comprehensive study to date.

Research in context

Evidence before this study

Despite the endemic nature and high mortality of Lassa fever in west Africa, few large-scale, retrospective, clinical studies are available, with none from Nigeria where the virus is most diverse and outbreaks occur frequently. We searched PubMed and Google Scholar for articles published until June, 2017, using the following terms in various combinations, in English: “Lassa fever”, “clinical manifestation”, “retrospective study”, “case-control”, “case report”, “epidemiology”, and “pathogenesis”, “kidney”, “liver”, and “organ involvement”. We assessed the citations for additional materials. These searches yielded 30 papers published since 1970. Only two studies included more than 200 confirmed cases of Lassa fever; one from Sierra Leone with data collected between 1977 and 1979 and the other from Liberia with data collected between 1980 and 1986. This situation indicates a gap in up-to-date medical knowledge of Lassa fever, particularly in Nigeria.

Added value of this study

Our observational cohort study was done on the most comprehensive clinical datasets of Nigerian Lassa fever to date, which includes 291 patients treated in the Lassa fever ward at Irrua Specialist Teaching Hospital in Edo State, Nigeria, between Jan 3, 2011, and Dec 11, 2015. This dataset includes clinical signs and symptoms before admission and at presentation, vital signs and complications during treatment, and detailed laboratory results (haematology and blood chemistry) at presentation and during treatment. Our new findings are supported by earlier reports from the Irrua Specialist Teaching Hospital, which were done on smaller cohorts with less laboratory data. Furthermore, and more importantly, we found consistent evidence of intrinsic acute kidney injury in Lassa fever, an important contributor to severe illness and increased mortality.

Implications of all the available evidence

The importance of kidney injury in the prognosis of Lassa fever suggests that anticipating renal involvement earlier in the clinical course could lead to more effective interventions during treatment. These results provide a detailed picture of Lassa fever manifestation in a large cohort of Nigerian patients and show how its pathophysiology could be distinct from regions affected by other strains of Lassa virus.

Despite the epidemic risk, little is known about Lassa fever in Nigeria. The circulating virus in Nigeria is more diverse and genetically distinct than the virus seen elsewhere. Outbreaks frequently occur in Nigeria and 38% of cases were fatal in the outbreak in 2015.12 Sequencing studies have shown that the virus is highly divergent and more diverse than other haemorrhagic fever-causing viruses in the region, with a strain variation of up to 32%.13 This variation is comparable with Crimean-Congo haemorrhagic fever virus, the most genetically diverse of the arbovirus family, which reaches 30% sequence difference among isolates.14 By contrast, the genetic diversity of Ebola virus is less than 3% across all sequenced strains, and of the Rift Valley fever virus is 5%.15 The high diversity of LASV might explain the observed variability of Lassa fever's clinical presentation as well as possible regional differences. Earlier studies16 at Irrua Specialist Teaching Hospital revealed that patients who died consistently had higher blood urea nitrogen and serum creatinine concentrations than did survivors, and severe systemic disease included acute kidney injury. However, studies done since 1970 across Sierra Leone, Guinea, Liberia, and Nigeria show varying degrees of renal involvement (appendix).

We present one of the largest and most detailed clinical datasets of Nigerian Lassa fever to date. This dataset includes clinical signs and symptoms before admission and at presentation, vital signs and complications during treatment, and detailed laboratory results (haematology and blood chemistry) at presentation and over the course of the treatment. We derived logistic regression models from these data to quantify the contributions of individual organ involvement to the overall mortality risk in Lassa fever. We also investigated the relative contributions of different clinical manifestations to the mortality risk at admission, quantified the incidence of various complications affecting patients, and assessed the importance of renal involvement as a feature of Lassa fever. Furthermore, we hypothesised that LASV was the direct cause of intrinsic renal damage for a subset of the patients with Lassa fever in our cohort.

Section snippets

Data collection and management

The study population consists of all consecutive patients with clinical and laboratory records treated in the Lassa fever ward of Irrua Specialist Teaching Hospital from Jan 3, 2011, to Dec 11, 2015. Patients were accepted into the ward after testing positive for LASV by targeting the glycoprotein complex gene with Qiagen OneStep RT-PCR Kit reagents (Qiagen, Hilden, Germany, number 210210 or 210212).16 Patients were diagnosed and clinically tested at Irrua Specialist Teaching Hospital by use of

Results

The dataset comprises 291 patients, including 170 men and 121 women, with an average age of 35 years. 284 (98%) patients had known outcomes (died or survived) and seven (2%) were discharged against medical advice. The overall case-fatality rate is 24% (68 of 284 patients), which is substantially lower than the 69% case-fatality rate observed in the eastern province of Sierra Leone. The differences in mortality across the catchment area of Irrua Specialist Teaching Hospital (figure 1) are not

Discussion

Our study introduces the most complete clinical and laboratory dataset of patients with Lassa fever available to date, describes logistic regression models of patient outcome, identifies independent predictors of death, and characterises the involvement of specific organs in the pathophysiology of Lassa fever. This study has the largest clinical dataset from Nigeria, where LASV is most diverse and annual outbreaks of Lassa fever are observed. Given the wide variability of clinical

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