A Surge in Malaria Cases in the Eastern Health Region of Saudi Arabia During the COVID-19 Pandemic

Background Malaria transmission was stopped on most of the vast area of the Kingdom of Saudi Arabia. However, the pandemic of coronavirus disease (COVID-19) has negatively affected the efforts to control malaria. For instance, COVID-19 was reported to induce a relapse of malaria that is caused by Plasmodium vivax. Furthermore, physicians’ attention toward COVID-19 can only result in neglect and delayed diagnosis of complicated malaria cases. These factors, among others, might have contributed to an increase of malaria cases in Dammam, Saudi Arabia. Thus, this study was conducted to examine the effects of COVID-19 on malarial cases. Methods The medical records of all patients who were treated at Dammam Medical Complex for malaria between July 1, 2018, and June 30, 2022, were reviewed. Malaria cases were compared between the pre-COVID-19 period (between July 1, 2018, and June 30, 2020) and the COVID-19 period (between July 1, 2020, and June 30, 2022). Results A total of 92 malaria cases occurred in the total study period. There were 60 cases of malaria in the COVID-19 period as opposed to only 32 cases in the pre-COVID-19 period. All the cases were imported from the endemic Saudi southern areas or from outside the country. Eighty-two patients (89.1%) were males. Most of them were Sundaneses (39 patients, 42.4%), Saudis (21 patients, 22.8%), and tribal peoples (14 patients, 15.2%). Fifty-four patients (58.7%) were infected with Plasmodium falciparum. Seventeen patients (18.5%) were infected with Plasmodium vivax. Another 17 patients (18.5%) had a mixed infection with both Plasmodium falciparum and Plasmodium vivax. A trend toward more infected stateless tribal patients was observed in the COVID-19 period compared to the pre-COVID-19 period (21.7% vs 3.1%). A similar trend was noticed for mixed malarial infections with both Plasmodium falciparum and Plasmodium vivax (29.8% vs 0%) with a P value of less than 0.01. Conclusion Malaria cases were almost doubled during the COVID-19 pandemic as compared to the pre-pandemic era signifying the negative effects of the pandemic on malaria epidemiology. The cases increased for a variety of causes that include alternation of health-seeking behaviors, changes in healthcare structures and regulations, and the interruption of malaria preventive services. Future research is needed to study the long-term effects of the changes imposed by the COVID-19 pandemic and to mitigate the effects of any future pandemic on malaria control. As two patients from our cohort were diagnosed with malaria based on blood smears, although they had negative rapid detection tests (RDTs), we recommend testing all the patients who are suspected to have malaria with both RDTs and peripheral blood smears.


Introduction
Globally, 229 million malaria cases and 409 thousand deaths from malaria occurred in 2019 [1]. In Saudi Arabia, malaria transmission was stopped on the majority of the vast area of the country, but it continues to be endemic in its southwestern region in Tohama coastal area, Jazan Region, and the Saudi Arabia-Yemen border [2][3][4] with the continuing conflict in Yemen as a contributing obstacle for the elimination of malaria in Saudi Arabia [5].
The pandemic of coronavirus disease  has negatively affected the efforts to control malaria as it has caused a shortage of antimalarial agents and disturbed malaria preventive services [1,6]. Moreover, travelers might not get adequate malaria prophylaxis for the fear of getting COVID-19 if they visited the hospitals during the pandemic [7]. Furthermore, physicians' attention toward COVID-19 can only result in neglect and delayed diagnosis of complicated malaria cases [8].
Hence, this study was conducted to evaluate the effects of COVID-19 on malaria cases in Dammam, Saudi Arabia.  15.2%). The mean ± standard deviation for the patients' age was 33.7 ± 11.1 years. Twenty patients (21.7%) had a personal previous history of malaria. Fever (92 patients, 100%) was the most common presenting symptom, followed by body pains (32 patients, 34.8%) and fatigue (19 patients, 20.7%). The mean ± standard deviation for the patients' duration of symptoms prior to presentation was 7.0 ± 7.2 days with a median of 5.0 days and a range from one day to 60 days. Eighty-one patients (88.0%) were admitted to the hospital for management. The remaining patients (11 patients, 12.0%) were managed in the emergency room. The mean ± standard deviation for the patients' parasitemia level was 2.2 ± 3.0% with a median of 1.0% and a range from 0.001% to 16.0%. Most of the patients were infected with Plasmodium falciparum alone (54 patients, 58.7%) followed by isolated Plasmodium vivax infection (17 patients, 18.5%) and mixed infection of both Plasmodium falciparum and Plasmodium vivax (17 patients, 18.5%). Only one patient (1.1%) was infected with Plasmodium ovale. The type of malaria parasite was not identified in three (3.3%) patients ( Figure 1).

FIGURE 2: Malaria cases and periods of presentation (n = 92).
The patient's demographics and clinical presentations are given in Table 1.  patients (87.0%) with a mean platelet count of 88.3 ± 59.0 × 10 9 /L. Thirty patients (32.6%) had a hemoglobin of less than 12 g/dl. Leukopenia and leukocytosis were found in 19 (20.7%) and 7 (7.6%) patients, respectively. The patients' initial total and direct bilirubin levels were 2.6 ± 2.9 and 1.4 ± 2.4 mg/dl, respectively. The patients' initial laboratory results are given in Table 2.

TABLE 3: Patients' antimalarial medications (n = 92).
Twenty-two patients (23.9%) developed an acute kidney injury (AKI). Shock or sepsis occurred in seven patients (7.6%). Four patients (4.4%) had cerebral malaria with all of them having impaired consciousness and delirium and none of them developing seizures. One patient (1.1%) infected with Plasmodium falciparum developed myocarditis and heart failure [10]. A different patient (1.1%) infected with Plasmodium vivax presented with a splenic rupture. Both diabetic ketoacidosis and hypoglycemia occurred also in one patient (1.1%). The mean ± standard deviation for the duration from presentation to discharge for the hospitalized patients was 5.1 ± 4.1 days. Six patients (6.5%) were admitted to the intensive care unit (ICU) and stayed there for 2.6 ± 2.0 days. Five patients (5.4%) relapsed after discharge and were readmitted, with a mean duration from discharge to readmission of 43.4 ± 35.5 days. A single patient died (1.1%) in this cohort. This patient was infected with Plasmodium falciparum, his diagnosis got delayed after multiple emergency room visits, and his presentation included cerebral malaria (impaired consciousness, sleepiness, and vertigo) with severe hypotonic hyponatremia (117 mmol/L). The patients' complications and outcomes are given in Table  4.  A trend toward more infected stateless tribal patients was observed in the COVID-19 period compared to the pre-COVID-19 period (21.7% vs 3.1%). A similar trend was noticed for mixed malarial infections with both Plasmodium falciparum and Plasmodium vivax (29.8% vs 0%) with a P value of less than 0.01 ( Figure 3). There were no other significant differences between the two groups.  . Expectedly, they stayed longer in the hospital (7.9 ± 6.6 vs 4.1 ± 1.9 days, P value <0.001). The detailed comparison between the malaria patients based on developing AKI is shown in Table 6.

Discussion
Malaria cases in Dammam Medical Complex have increased by 93% in the COVID-19 period compared to the pre-COVID-19 period. A similar surge of malaria cases was also noticed in other countries like Zimbabwe [11], Gabon [12], Bhutan [13], and Peru [14]. Likewise, there was a report of increasing cases of severe malaria following the COVID-19 pandemic among the French Armed Forces during their missions in the Sub-Saharan African countries [15]. Relatedly, 2021 was the highest year of imported malaria cases in Shanghai over the past 10 years [16].
Many factors might explain this surge in malaria cases, both locally in Saudi Arabia and globally following the COVID-19 pandemic. For instance, COVID-19 was reported to induce a relapse of malaria that is caused by Plasmodium vivax [17][18][19] and Plasmodium ovale [20]. Similarly, the Pfizer BioNTech (BNT162b2) COVID-19 vaccine, the first COVID-19 vaccine to be approved in Saudi Arabia [21] and the most used COVID-19 vaccine by Saudi citizens [22], was reported to cause recrudescence of subclinical chronic malarial infections [23]. Additionally, malaria patients may complain from fever, headache, and body pains, which are also reported commonly due to COVID-19. In consequence, the concerns of getting infected by the COVID-19 virus during the pandemic might have driven more of these patients to seek medical care and, hence, be diagnosed with malaria at the end [11].
The increase in malaria cases in the Dammam Medical Complex might also be related to the changes imposed on the healthcare system following the COVID-19 pandemic. Other centers in the Eastern Province were used to diagnose and treat some mild malaria patients with oral antimalarial agents. Following the pandemic, some of these centers were changed into COVID-19 centers and stopped managing non-COVID-19 patients. Others might have run out of hydroxychloroquine following the initial, false reports that it was effective against COVID-19 and might have been left with no other options to treat malaria. It is likely that the patients who would normally be treated at such centers were all referred to the Dammam Medical Complex, as it is the main malaria hospital in the region. Similarly, some private and specialized centers and hospitals tried to maintain a non-COVID-19 environment and referred all febrile patients who were suspected to have COVID-19 to Dammam Medical Complex, the primary COVID-19 hospital in the Eastern Province. Additionally, the royal order to treat all confirmed and suspected COVID-19 patients for free might have encouraged more patients who reside in Saudi Arabia illegally, a major vulnerable yet underrepresented group [5], to seek medical care. It is likely also that COVID-19 caused restrictions to international travel, changing the usual travel destinations and leading to more local infections, as evident by the increasing number of patients who acquired malaria from visiting the endemic Saudi Arabia's southern areas during the COVID-19 period.
In Africa, the interruption of malaria services by the COVID-19 pandemic disturbed the mass distribution of long-lasting insecticide-treated nets (LLINs), and impacted many focal preventative measures such as seasonal malaria chemoprevention (SMC) and indoor residual spraying of insecticides (IRS) [1,13,24]. It also resulted in decreased access to effective antimalarial treatment [1]. It is expected that the preventive measures in Saudi Arabia have also been interrupted following the pandemic, though to a lesser degree.
One of the long-term effects of the COVID-19 pandemic on malaria control is the growing vaccine hesitancy that was associated with the introduction and distribution of COVID-19 vaccines. This hesitancy could hinder plans for developing and administering malaria vaccines [25]. Moreover, it is known that chloroquine sensitivity in Plasmodium falciparum could re-emerge with time, as occurred in the Jazan Region, where onethird of the isolates returned to be susceptible [26]. However, the wide use of chloroquine and hydroxychloroquine during the initial stages of the COVID-19 pandemic could delay their sensitivity reemergence [6].
The deadliest type of malaria, Plasmodium falciparum, was the predominant malaria species in this study presenting either alone or mixed with Plasmodium vivax in 77% of the study patients. This matches the published data that found it to be the most common malaria type in Saudi Arabia [3,5]. Plasmodium falciparum predominated in both the pre-COVID-19 and the COVID-19 periods. However, rates of mixed infections increased during the COVID-19 period. All 17 cases of mixed Plasmodium falciparum and Plasmodium vivax infections in the study were in the COVID-19 period. This unmatched increase in mixed infections should be interpreted with cautions as the identification of the malaria species was not validated in a reference laboratory.
Apart from the presumed effects of COVID-19 on malaria cases, the study revealed deficiencies in primaquine prescriptions for patients infected with Plasmodium vivax and Plasmodium ovale. About 29% of these patients were not given primaquine to eradicate hypnozoites after the initial antimalarial therapy resulting in five cases of relapse. A portion of these patients was managed without any involvement from infectious disease fellows and consultants signifying the importance of infectious disease consultation in managing malaria cases. Regardless, the main reason that primaquine was not given to many patients was that the glucose-6-phosphate dehydrogenase (G6PD) enzyme status was not readily available at the time of discharge. Fastening the release time of the G6PD results is expected to improve the rates of primaquine prescriptions.
It was also noted in this study that physicians should not rely too much on malaria rapid detection tests (RDTs) as they do not always detect malarial infections [27,28]. Two patients from our cohort were diagnosed with malaria based on blood smears, although they had negative RDTs. Both patients were from Sudan, a country among many that reported cases of RDT-negative malaria due to parasites carrying hrp2/3 deletions [29,30]. All patients with a strong epidemiological link to malaria should be tested with both rapid antigen detection tests and peripheral blood smears when they are suspected to have malaria.
Our study has several limitations that should be considered. The first is that the retrospective nature of the study makes it prone to information bias from the potentially missing data in the patient's medical records.
The second is that the study was conducted in a single center, especially since some malaria cases in the Eastern Province of Saudi Arabia are treated in the primary health care centers, the university and military hospitals, and the private sector. Lastly, the Eastern Province is not an endemic malaria area in Saudi Arabia. All the cases were imported from the endemic Saudi southern areas or from outside the country. Thus, it would be more informative if a similar study was conducted in Tohama coastal area, Jazan region, and the Saudi Arabia-Yemen border to study the complete effects of the COVID-19 pandemic in Saudi Arabia.

Conclusions
Malaria cases were almost doubled during the COVID-19 pandemic as compared to the pre-pandemic era, signifying the negative effects of the pandemic on malaria epidemiology. The cases increased for a variety of causes that include alternation of health-seeking behaviors, changes in healthcare structures and regulations, and the interruption of malaria preventive services. Future research is needed to study the longterm effects of the changes imposed by the COVID-19 pandemic and to mitigate the effects of any future pandemic on malaria control.
As two patients from our cohort were diagnosed with malaria based on blood smears, although they had negative rapid detection tests (RDTs), we recommend testing all the patients who are suspected to have malaria with both RDTs and peripheral blood smears.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Dammam Medical Complex Institutional Review Board issued approval IM-03. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. to have influenced the submitted work.