Coronaviruses are enveloped RNA viruses that are widely spread among humans, certain other mammals and birds, and that contribute to respiratory, enteric, liver, and neurological disorders.1–3 At first, an unknown pneumonia case was identified on December 12, 2019, and possible influenza was distinguished from other coronaviruses by laboratory testing.4,5 The Chinese government announced on January 7, 2020, that a novel type of coronavirus (novel Coronavirus, nCoV) was isolated.6 The World Health Organization (WHO) announced on January 30, 2020 the occurrence of COVID-19 as the sixth worldwide public health emergency, after H1N1 (2009), Ebola in West Africa (2014), polio (2014), Zika (2016), and Ebola in the Democratic Republic of Congo (2019).7
H1N1 influenza is a new highly contagious respiratory system infection that received wide recognition in Mexico in April 2009. It has had a swift spread in numerous countries, leading to the WHO’s raising the warning stage to phase-6 (pandemic point) by June 2009.8 This disease has the potential to be transmitted 1 day before to 5 days after its symptoms emerge. Today, this virus is reported from many countries including Iran. Much like those of the H1N1 epidemic, the underlying problems such as diabetes mellitus, immunocompromised condition, heart failure, and obesity are among the major risk factors for the novel COVID-19 infection, the outbreak of which occurred in China during the Chinese New Year, also known as Spring Festival, the most famous conventional festival in China, when nearly 3 billion individuals travel countrywide. These conditions provided favorable grounds for the rapid transmission of this markedly contagious disease and also gave rise to major difficulties in preventing and controlling the epidemic.9 Both H1N1 and COVID-19 affect the respiratory tract and have some common clinical signs, the most prevalent of which include fever, cough, breathing difficulty, and sore throat, often accompanied by medical problems associated with the stomach and intestine such as diarrhea, and both vomiting and diarrhea. Both of these conditions contribute to the development of other problems such as pneumonia, acute respiratory distress syndrome, and even mortality to such an extent that H1N1 alone has led to approximately 284,500 deaths since the outbreak of the infection in 2009.10
Although the COVID-19 virus bears no resemblance to the influenza virus, they are almost identical with respect to disease pathogenesis and clinical symptoms. In the present study, we conducted a survey of all the articles on the clinical features and laboratory findings of patients with either H1N1 or COVID-19 up to February 19, 2020. Subsequent to rigorous evaluation, a total of 4 published articles with clinical characteristics and laboratory-obtained findings of patients with H1N1 were identified and incorporated into this study. Tables 1 and 2 present the summary of the included clinical studies. Subsequently, we performed a comparison between patients with H1N1 and COVID-19 in terms of the clinical characteristics and laboratory findings.
TABLE 1 -
Clinical Characteristics and Laboratory Findings of 403 H1N1-infected Patients
||Saleh et al11 (n=40)
||Najafi et al12 (n=41)
||Mikić et al13 (n=98)
||Mu et al14 (n=224)
||Tabriz (North of Iran)
||Mazandaran (North of Iran)
| Cardiovascular disease
| Respiratory disease
|Symptoms and signs
| Sputum production
| Sore throat or pharyngalgia
|Duration of onset to hospital admission (d)
| Hemoglobin (mg/dL)
||Low in 15 (15.3)
| White blood cell count (×10/L)
||Low in 15.3%, high in 7.1%
||Low in 11.6%, high in 5.6%
| Neutrophil count (×10/L)
||Low in 8.5%, high in 51.8%
| Lymphocyte count (×10/L)
||Low in <20%, high in >40%
| Platelet count (×10/L)
||Low in 17 (17.3)
| Creatinine (μmol/L)
||High in 20 (20. 4)
| ALT (U/L)
||High in 12 (12.2)
| AST (U/L)
| ESR (mm/h)
Data are n (%), mean±SD.
ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; ESR, erythrocyte sedimentation rate; NA, not available.
TABLE 2 -
Treatment and Outcomes of 403 H1N1-infected Patients
||Saleh et al11 (n=40)
||Najafi et al12 (n=41)
||Mikić et al13 (n=98)
||Mu et al14 (n=224)
|Invasive mechanical ventilation
Data are n (%).
NA indicates not available.
The clinical features and laboratory findings on patients with H1N1 have been extensively outlined in 4 fairly large-scale trials. Here, after comparing data related to the accessible comparable studies about COVID-19, we reported the clinical and laboratory outcomes of the group of 403 patients with H1N1 (Table 1).
The H1N1 virus was a pandemic that caused a global wave of panic and anxiety almost like the current situation in relation to the new coronavirus (Fig. 1). The prevalence of COVID-19 is by far larger than that of H1N1 in 2009. Worldwide, although with a death rate of 0.02%, H1N1 affected between 700 million and 1.4 billion individuals. Comparatively, the novel coronavirus infection is more lethal than H1N1, for which a death toll of 3.4% was recorded by WHO in 2019. The mortality rate of COVID-19 was initially claimed to be 15%. Later tests have, however, demonstrated lower mortality rates ranging from 4.3% to 11%.15,16 Until August 7th, 2020, a total of 19,301,624 patients have tested positive for COVID-19 around the world.17
Nevertheless, the estimates of mortality rates are reported on the basis of the number of deaths as per the number of confirmed COVID-19 cases, which does not represent the actual death rate exactly. The reason is that the patients who die of this disease have been infected with it pretty much earlier than their death time; therefore, the denominator of the mortality rate should be the total number of COVID-19-infected patients along with the number of those who die. According to one study, out of all the confirmed cases, a total of 1023 deaths were reported, with an overall case-fatality rate of 2.3%. It should also be noted that 81% of the reported deaths were among patients older than 60 years of age. The mortality of patients aged 60 to 69, 70 to 79, and over 80 years has rates equaling 3.6%, 8.0%, and 14.8%, respectively. In addition, the mortality rate for the patients with critical conditions was 49%.7 It can also be noted that it is difficult to assess the magnitude of the distribution of COVID-19 beyond China. Given the 1 million or so Chinese expatriates residing on the continent, a considerable number of COVID-19 cases have been reported outside of China. The scope and reliability of the medical tests and screening would impact on the dissemination of confirmed cases. Furthermore, according to the findings of a modeling study published in The Lancet on January 31, each COVID-19-infected patient infects a further 2.68 individuals.
The mean age of all the influenza patients included in the present study was 30.9±13.7 years (range, 1 to 80 y), and 57.3% of the patients were males (n=231). Also, the most typical symptoms were, respectively, fever (94.7%; n=382), followed by cough (80.1%; n=323), dyspnea (9.9%; n=40), myalgia (25.3%; n=102), headache (42.4%; n=129) and diarrhea (9.1%; n=37), rhinorrhea (33.4%; n=135), sore throat, or pharyngalgia (44.9% n=181).
A number of 41 patients admitted at the hospital had tested positive for COVID-19 infection until January 2, 2020. Most of the infection-positive patients were men [30 (73%)]; less than half had underlying conditions [13 (32%)] such as diabetes [8 (20%)], hypertension [6 (15%)], and cardiovascular disease (CVD) [6 (15%)]. It is noteworthy that the prevalent manifestations of the disease at the initial phases were fever [40 (98%) of 41 patients], cough [31 (76%)], and myalgia or fatigue [18 (44%)], whereas less typical signs included sputum production [11 (28%) of 39], headache [3 (8%) of 38], hemoptysis [2 (5%) of 39], and diarrhea [1 (3%) of 38]. It is noteworthy that 22 (55%) of 40 patients developed dyspnea.18 This result was consistent with our study. The aforementioned finding coincided with that of our study. Moreover, the study by Liu et al19 revealed that out of 137 patients, 61 males and 76 females, with an age range of 20 to 83 years, median age 57 years, none had been exposed, in any way, to the Huanan Seafood Wholesale Market. Also, the main primary indications were fever (112/137, 81.8%), coughing (66/137, 48.2%), and fatigue or muscle pain (44/137, 32.1%), accompanied by other less common initial symptoms seen at low frequency, including headache, heart palpitations, and diarrhea. The duration of the incubation period is one distinction between H1N1 and COVID-19. Although the former has a limited incubation period ranging from 1 to 2 days, the incubation period for the latter lasts nearly about 5 days or so.
Given higher prevalence of H1N1 and COVID-19 infection in men (Table 1) than in women with ratios of (male: female) 1.3:1, and 2.7:1, respectively, the specific trend of transmission and dissemination for H1N1 and COVID-19 may have been focused on a particular sex for each illness.18 The predominance of COVID-19 among males shows that the possibility of exposure to the infectious agent is much higher in males than in females in most communities. In addition, most males, who tested positive for the virus and died, also had underlying medical conditions, potentially accounting for the severity of infected cases due to exposure to the infectious agent in older males than in females in most nations.20
In general, the reason why outcomes in males and females are different is unknown. According to a number of studies, estrogen, which is likely to protect females from worse outcomes after severe acute respiratory syndrome and coronavirus (SARS-CoV) infection, accounts for the different outcomes among men and women.21,22 The other possible reason for the mentioned discrepancy could be that the severity of the infection was much higher in males. Liang et al23 found that out of patients with severe COVID-19, those with cancer were more susceptible to COVID-19. Moreover, the other study carried out by Li et al24 demonstrated that, compared with women, a larger number of men were infected with COVID-19, combined with bacteria or influenza virus at the same time, hence the possibility of higher risk among male patients.
Also, the findings obtained from the study by Rothberg et al25 indicated that bacteria-induced infection was a common pulmonary complication of influenza. Also, the findings obtained by Li et al24 indicated that positive H1N1 antibodies were found in 5 male patients, but not in female ones. Nonetheless, men were shown to have a higher rate of increased procalcitonin, all suggesting that male patients suffering from severe COVID-19 are vulnerable to secondary virus-induced or bacteria-induced infections, leading to higher rates of utilization of advanced antiviral therapy and antibiotics. The results of another study revealed that 71% of the COVID-19-positive patients received antibiotic treatment, although no comparisons were made between men and women.16 Furthermore, Wu et al26 examined the chest computed tomography (CT) findings in 80 patients with the confirmed COVID-19 and how it is associated with clinical features. Their findings showed that adults comprised most of the patients and that the numbers of either male or female cases did not differ significantly at all. Consequently, thorough study of why and what type of influenza virus or bacteria are more likely to co-occur with COVID-19 in men would yield significant clinical results.
Aged mostly 21 to 50 years, patients infected with H1N1 were typically from an average population who were in their early 40s. However, it is older adults with a median age of 50 years who are mainly infected by COVID-19.27 It was speculated that this variation is due to the production in older individuals of cross-reactive influenza antibodies from previous influenza exposures. To date, the clinical consequences of COVID-19 for children have been few based on the reports. The little set of reports from China indicate that COVID-19-positive children may have moderate signs and other severe complications (acute respiratory distress syndrome and septic shock), although highly uncommon.28–30 Research by Zhao et al31 examining a mathematical model to evaluate the transmissibility of the new coronavirus with respect to the age of individuals revealed the strong transmissibility of severe acute respiratory syndrome and coronavirus-2 (SARS-CoV-2) among adults and older persons, but low transmissibility among children and adolescents.
Also, a recently carried out study in Shanghai indicated that 10 patients were aged 3 to 131 months (mean: 74 mo) and the male to female ratio was 1:1. Moreover, it showed that 8 (80%), 6 (60%), 4 (40%), 3 (30%), and 2 (20%) patients suffered from fever, cough, sore throat, stuffy nose, and sneezing and rhinorrhea, respectively. During the course of infection, no signs of diarrhea or dyspnea were reported in the patients. Also, it was shown that 8 children (80%) developed COVID-19 infection through direct contact with infected adults who had traveled to Wuhan or had exposure to infected people coming from Wuhan.32 Another research examined a total of 9 children aged younger than 1 year who were diagnosed with COVID-19 and were hospitalized in China from December 2019 to February 6, 2020.29 The reason for the small number of infected infants might be that they are less likely to be at risk of exposure or they are not diagnosed completely due to mild or asymptomatic disease, rather than their resistance to infection. Research has nevertheless demonstrated that children can develop COVID-19, although it was adults aged over 15 years who were the primary patients at the earlier stage of the COVID-19 outbreak.33,34 Seven of the 9 pediatric patients were female, which is not in agreement with earlier research that reported higher infection levels in men than in women.6,15,16 Much like other respiratory diseases which pose threats to people, this severe infectious disease can put other groups of children such as those who suffer from chronic health problems at a greater risk and it is hypothesized that female children are more vulnerable to 2019-nCoV than male ones. However, this contention needs more study to be confirmed.
It appears that patients who are older and suffer from comorbidities are the group most vulnerable and prone to high-risk diseases caused by SARS-CoV-2, which is the name suggested for the causative virus.35
WHO has asserted that older age and underlying medical problems play a huge role in the increased risk of severe infection, suggesting that patients with such conditions, for example, respiratory tract and heart disease, are more expected to undergo hospitalization.36 The studies included for analysis revealed that respiratory disease and diabetes were the most prevalent underlying conditions in adult patients, followed by CVD. In another study, it was reported that the underlying medical conditions were observed in a number of 20 (48.8%) patients including 4 patients with asthma, 3 with diabetes mellitus, 2 with hypertension, 2 with heart failure, 2 with obesity (body mass index ≥30), 2 with a history of corticosteroid therapy, and one case with kidney transplantation along with immunosuppressive therapy.12 The influence of the underlying medical conditions was investigated for the first time by researchers in China, who analyzed a large sample of 1590 patients with COVID-19 nationwide with the laboratory-confirmed disease. They evaluated the way in which “comorbidities” (existing diseases) impact patients’ admission to intensive care and the likelihood of them being placed on a ventilator, or even death. On considering patients’ age and smoking status, the researchers discovered that 399 patients suffering from at least one additional condition such as CVDs, diabetes, hepatitis B, chronic kidney diseases, chronic obstructive pulmonary disease, and cancer were 79% more likely to require intensive care or respiratory care or both, or even to die, compared to those without comorbidities.37 The possibility of mortality in persons with cardiac diseases is due to the close interdependency of the heart and lung. With rapid inhalation and exhalation, the heartbeat increases automatically, but if the heart is already weak or a person has coronary atherosclerosis, there may be increased oxygen delivery needed. Flu cases can exacerbate the disease and increase patient admissions in hospitals. If a person’s immune system is weak, he or she will be more prone to developing a second infection, due to exposure to larger amounts of pathogens. Diabetes and the resultant medical conditions contribute to the downregulation of innate and humoral immune systems through diminishing the function of T cells and neutrophils.38 Therefore, patients with cardiovascular and diabetic diseases should ensure that their blood pressure is under control.
In our study, the magnitude of white blood cells (WBC) in most of the patients with H1N1 was normal; however, leukopenia and leukocytosis were reported in 12.7% and 6.2% of the patients, respectively. In one study, all the patients were requested to undergo the complete blood count test, the results of which showed that 11 individuals (26.8%) had leukopenia and only 3 (7.3%) had leukocytosis. Also, 15 patients (36.6%) were reported to have relative lymphopenia (≤21% of WBCs).12 According to a number of studies, neutrophils play a major role in the inhibition of viral replication in the early and late stages of infection with influenza, and, moreover, it was found that decreased neutrophil activity is likely to lead to severe outcomes even in cases of medium viral strain virulence.39 Huang et al18 showed that COVID-19-diagnosed patients admitted to a designated hospital in Wuhan had traces of leukopenia [WBC count <4×109/L; 10 (25%) of 40 patients] and lymphopenia [lymphocyte count <1.0×109/L; 26 (63%) patients] in their blood counts. Another comprehensive systematic review of 72 retrospective studies on COVID-19-confirmed patients revealed that out of 2387 patients, 1498 (62.8%) cases showed lymphopenia (lymphocyte count <1.0×109/L), whereas out of 2091 patients, a total of 1354 (64.8%) cases had an increased level of C-reactive protein. Similarly, results obtained from a systematic and meta-analysis on 101,905 patients with 2019-nCoV demonstrated lymphopenia (0.93×109/L, 95% confidence interval: 0.83-1.03×109/L, n=464) and abnormal C-reactive protein (33.72 mg/dL, 95% confidence interval: 21.54-45.91 mg/dL, n=1637) as the main laboratory findings in COVID-19-confirmed patients. Therefore, it could be said that both H1N1 and COVID-19 diseases show leukopenia as the main laboratory findings, although H1N1 patients showed mild leukopenia.
In one of the included studies, the most common radiologic pulmonary finding was bilateral focal ground-glass opacity (GGO) (30%), followed by peribronchovascular appearance (15%), bilateral diffuse GGO (12.5%), unilateral diffuse GGO (12.5%), unilateral focal GGO, and bilateral thromboembolism (7.5%) documented by CT angiography. Overall, it has been shown that chest imaging in 4 cases was normal.11
In many studies, GGOs and consolidations or a combination of the 2 were the most frequent outcomes in the CT scan for patients with H1N1. The involvement was usually bilateral, without axial or craniocaudal distribution predominance.40 Chest CT scans for 21 symptomatic COVID-19-infected patients from China were analyzed, highlighting the identification and characterization of the most widespread findings. Common data obtained from CT scans included bilateral pulmonary parenchymal ground-glass and consolidative pulmonary opacities, which were also accompanied by a peripheral lung distribution and a rounded morphology. It should be noted, however, that the findings did not include any signs of lung cavitation, discrete pulmonary nodules, pleural effusions, and lymphadenopathy.41 Intensified reduction in the lung parenchyma that contributes to the covering up of the vascular outlines and adjoining airway walls is called consolidation, and moreover, the insignificant increase in the attenuation of the lung parenchyma that has nothing to do with the concealment of the vessels and adjacent airway walls is referred to as GGO.42 Moreover, chest x-ray provides adequate information for defining the approach in most of the patients with H1N1 and 2019 novel coronavirus. Furthermore, most of the sufficient data required to define the mechanism in the patients with H1N1 and COVID-19 are provided by chest x-ray. Although it is by means of the clinical profile and virus identification that the viral infection is diagnosed, identification of some imaging characteristics of the disease can be beneficial, particularly in patients showing atypical clinical signs.41 Consequently, gaining an understanding of the mechanism provided by imaging features of the disease assumes the utmost significance in clinical practices. The identification of pulmonary indications and radiologic characteristics contributes to the diagnosis, treatment, and isolation of patients early so as to halt the spread of this highly contagious respiratory tract infection.
TREATMENT OF COVID-19
It is widely believed that there is an urgent demand for suitable therapeutics to cure the new COVID-19 disease. The lethal nature of the infection has produced a pronounced sense of fear in patients and people in general. All the nations dealing with the COVID-19 situation place enormous emphasis on preventing the infection from being rapidly spread. Moreover, the infection is a new type of respiratory disease with a very lethal nature, and even though the existing drugs have been successful in partially managing the symptoms, no definite line of treatment and therapeutics have yet been introduced for this infection. However, H1N1 is said to be vulnerable to neuraminidase inhibitors and, accordingly, it has been suggested that oseltamivir be used as prophylaxis for high-risk groups. Mostly comprised of resting in bed, use of cough suppressants, increased fluid consumption, and use of antipyretics and analgesics, the treatments for H1N1 infection have fortunately been reassuring (e.g., acetaminophen, but no steroidal anti-inflammatory drugs) for fever and myalgias. The Food and Drug Administration (FDA) has confirmed the use of four antiviral drugs, which include Oseltamivir (Tamiflu), Zanamivir (Relenza), Baloxavir (Xofluza), and Peramivir (Rapivab), sometimes prescribed during the initial days when symptoms appear to minimize the intensity of signs and perhaps the risk of other resultant medical conditions.43,44 In the 4 pooled studies on 403 patients, it was indicated that 22 patients (12.2%) with H1N1 required invasive mechanical ventilation (Table 2). In addition, 45.4% of patients received antiviral treatment, and some of the other patients received antibiotics and corticosteroid treatment. According to a study by Rewar and colleagues, unless antiviral drugs are taken within the first 48 hours from the emergence of clinical signs, they will not be effective. However, they could also be used in severe or high-risk patients diagnosed early after this time frame. Belonging to a new class of drugs called neuraminidase inhibitors that are active against both influenza types A and B, oseltamivir (Tamiflu, Genentech) or zanamivir (Relenza, GlaxoSmithKline) are recommended by the Centers for Disease Control and Prevention (CDC).45 In the present study, of 403 H1N1-infected patients, 11 died and most of the deaths occurred in male and elderly patients.
Although H1N1 and coronavirus 2019 belong to different families, they have similar symptoms and diagnostic methods. Therefore, with regard to COVID-19 treatment, patients might receive the same treatment methods and medications used for H1N1 viruses. Several studies have confirmed similar treatments.46,47 Currently, no vaccine or antiviral treatment has been introduced for humans and animals infected by coronaviruses, hence the critical need for and significance of swiftly identifying drug treatment options in response to the outbreak of 2019-nCoV. Han and colleagues reported in their study that a man, aged 47 years, visited the People’s Hospital in Wuwei with complaints of 7 days of unexplained fever, and cough on January 21, 2020. The infection of the patient with coronavirus disease in 2019 was confirmed by reverse transcription-polymerase chain reaction. To prevent the replication of the virus, relieve asthma and phlegm, and to administer an empirical antibiotic treatment, combination therapy was initiated using lopinavir and ritonavir tablets (800/200 mg daily), methylprednisolone (40 mg daily), ambroxol hydrochloride (60 mg daily), recombinant human interferon alpha 2b (10 million IU daily), and moxifloxacin hydrochloride (0.4 g daily).
To date, treatments are being sought and will be tested through clinical trials. Remdesivir is a nucleotide analogue prodrug intracellularly metabolized to an analogue of adenosine triphosphate that inhibits viral RNA polymerases. Remdesivir has wide-spectrum activity against coronaviruses [eg, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV)] and has demonstrated prophylactic and therapeutic effectiveness in nonclinical models of these coronaviruses.48 The Beigel et al49 study demonstrated that remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with coronavirus disease 2019 (COVID-19) and evidence of lower respiratory tract infection. In this study, a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in 1063 adults hospitalized with COVID-19 with evidence of lower respiratory tract involvement was conducted.
Tocilizumab is another drug under investigation. Tocilizumab, an interleukin-6 inhibitor, can improve the inflammatory manifestations of severe COVID-19 and thus improve clinical outcomes. Rilinger et al,50 in their controlled trial study, reported that tocilizumab decreases the number of days that patients are dependent on mechanical ventilation and alleviates the vital need of assisted breathing via ventilators. In addition, this treatment could lead to fewer admissions to intensive care units.
Losartan is an angiotensin-converting enzyme (ACE) inhibitor used to treat hypertension.51,52 ACE inhibitors are used for a similar indication, but associated with a cough. Some different studies have shown that ACE inhibitors such as losartan could have a protective effect on some tissue injury due to systemic inflammatory diseases. Salari et al53 reported that losartan, by preventing the induction of overexpression of the inflammatory cytokine, may decrease the severity of the disease and duration of hospitalization. Losartan, by inhibiting these proteins, activates the production of the interferon-gamma and intracellular defense against the COVID-19 virus, thus increasing the resistance of persons to the coronavirus.50
It is noteworthy that the patient’s body temperature, pulse, and respiratory rate fluctuated slightly during the treatment and that the laboratory results showed an improvement, particularly lymphocyte count.54
To conclude, some of the evidence for the similarities and dissimilarities between COVID-19 and H1N1 is produced by the present study. Despite the discrepancies that exist in early symptoms, most COVID-19 patients show signs of fever and respiratory distreess. At present, whether or not an individual has traveled to the epidemic areas remains an important factor for diagnosis and should be considered for all patients with H1N1. Although at present the treatment is principally supportive and on the basis of medical signs, trials on vaccines and antivirals are taking place. Thus, given the fickle and unpredictable nature of current situation, it is recommended that healthcare providers follow the reports as provided by subsequent researches.
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